Wilson's Disease: Comprehensive Overview
Definition and Pathophysiology
Wilson's disease is an autosomal recessive inherited disorder caused by mutations in the ATP7B gene on chromosome 13, resulting in defective biliary copper excretion and pathological copper accumulation primarily in the liver and brain. 1
- The ATP7B gene encodes a copper-transporting P-type ATPase located in the trans-Golgi network of hepatocytes, responsible for copper excretion into bile and incorporation into ceruloplasmin 1
- Normal dietary copper intake (2-5 mg/day) exceeds metabolic needs, with homeostasis maintained exclusively through biliary excretion 1
- When biliary excretion fails, copper accumulates first in hepatocytes, then releases into blood causing deposition in brain, kidneys, eyes, bone, and muscles 2, 3
- The disease occurs worldwide with autosomal recessive inheritance 1, 4
Clinical Presentations
Hepatic Manifestations
Liver disease represents the most common initial presentation, ranging from asymptomatic elevation of transaminases to fulminant hepatic failure. 1, 5
- Early histological changes include mild steatosis (microvesicular and macrovesicular), glycogenated hepatocyte nuclei, and focal necrosis 1
- Progressive fibrosis leads to cirrhosis, typically macronodular, usually by the second decade of life 1
- Some patients may mimic autoimmune hepatitis with indistinguishable clinical and histologic features 1
- Hepatic steatosis can resemble nonalcoholic fatty liver disease 1
Acute Liver Failure Presentation
Acute liver failure from Wilson's disease has a distinctive pattern requiring urgent recognition for liver transplantation. 1, 5
The characteristic pattern includes:
- Coombs-negative hemolytic anemia with acute intravascular hemolysis 1
- Modest aminotransferase elevations (typically <2000 IU/L) 1
- Markedly subnormal or normal alkaline phosphatase (typically <40 IU/L) 1
- Coagulopathy unresponsive to parenteral vitamin K 1, 5
- Rapid progression to renal failure 1, 5
- Female predominance (2:1 ratio) 1
- Serum copper typically >200 μg/dL or 31.5 μmol/L 1
- Kayser-Fleischer rings may be absent in 50% of acute liver failure cases 1, 5
Neurologic Manifestations
Neurologic disease manifests as motor abnormalities with Parkinsonian features, including dystonia, hypertonia, rigidity, tremors, and dysarthria. 1, 3
- Disabling symptoms include muscle spasms leading to contractures, dysarthria, dysphonia, and dysphagia 1
- Rare presentations include polyneuropathy or dysautonomia 1
- Kayser-Fleischer rings are present in nearly all neurologic cases 5
- Brain MRI shows basal ganglia abnormalities in 77.7% of patients, with increased density on CT and hyperintensity on T2 MRI 1, 5
- Significant brain imaging abnormalities may be present before symptom onset 1
- The disease appears associated with dopaminergic deficit 3
Psychiatric Manifestations
Psychiatric symptoms include irritability, depression, and deterioration of work performance. 2, 3
Ophthalmologic Findings
Kayser-Fleischer rings are golden-brown copper deposits in Desçemet's membrane of the cornea, present in 50-62% of hepatic presentations and nearly all neurologic cases. 1, 5, 3
- Must be identified by experienced observer using slit-lamp examination 5
- Lunulae ceruleae (bluish discoloration of lunulae) rarely detected but suggestive 1
Age of Presentation
Wilson's disease should be suspected in patients aged 3-45 years, though cases can occur from age 5 to the eighth decade. 5, 6
- The disease is not limited to children and young adults but may present at any age 1
- In one series, five patients were diagnosed over age 40, with age range 7-58 years 6
Diagnostic Approach
No single test definitively confirms or excludes Wilson's disease; diagnosis requires multiple complementary investigations. 5
Initial Screening Tests
Serum ceruloplasmin <20 mg/dL is suggestive but not diagnostic, as it can be normal in 5-15% of patients. 1, 7
- Low ceruloplasmin has poor predictive value in acute liver failure 1
- Normal ceruloplasmin does not exclude Wilson's disease 1
24-Hour Urinary Copper
Urinary copper excretion >100 μg/24 hours (>1.6 μmol/24 hours) is highly suggestive of Wilson's disease. 5
- In acute liver failure, urinary copper is greatly elevated (range 844-9375 μg/24 hours) 6
- Results may not be available in timely manner for acute presentations 1
Hepatic Copper Quantification
Hepatic parenchymal copper content >250 μg/g dry weight is diagnostic and should be obtained when diagnosis is not straightforward, particularly in younger patients. 1, 5
- Normal hepatic copper (<40-50 μg/g dry weight) almost always excludes Wilson's disease 1
- Intermediate concentrations (70-250 μg/g) require further diagnostic testing, especially with active liver disease 1
- At least 1-2 cm of biopsy core length should be submitted for accurate measurement 1
- In cirrhosis, copper distribution is often inhomogeneous, leading to potential sampling error 1
- Transjugular liver biopsy circumvents technical problems in patients with decompensated cirrhosis or severe coagulopathy 1
- Absence of histochemically identifiable copper does not exclude Wilson's disease 1
Slit-Lamp Examination
Slit-lamp examination for Kayser-Fleischer rings must be performed by an experienced observer in all suspected cases. 5
ATP7B Mutation Analysis
Whole-gene sequencing detects mutations in 84.4% of alleles and should be performed when diagnosis remains uncertain after clinical and biochemical testing. 1, 5
- Haplotype analysis or specific mutation testing can be used for family screening of first-degree relatives 1
- Clinical geneticist may be required to interpret results 1
- Genetic diagnosis is difficult without family studies due to many different mutations causing the disease 4
Neurologic Evaluation and Brain Imaging
Neurologic evaluation and brain MRI should be considered prior to treatment in all patients with neurologic Wilson's disease and any patient with neurological symptoms consistent with the disease. 1
- MRI is more sensitive than CT in detecting basal ganglia lesions 1
- Consultation with neurologist or movement disorder specialist should be sought for patients with evident neurologic symptoms 1
Radiocopper Studies
Radiocopper incorporation studies show significantly reduced incorporation into ceruloplasmin in all homozygotes but are rarely used due to difficulty obtaining isotope. 1
Differential Diagnosis Pitfalls
All children with apparent autoimmune hepatitis and any adult failing to respond rapidly to corticosteroid treatment must be carefully evaluated for Wilson's disease. 1, 5
- Patients with Wilson's disease may have clinical features and liver biopsy findings indistinguishable from autoimmune hepatitis 1
- Occasional patients may benefit from brief corticosteroid course along with specific Wilson's disease treatment 1
- In acute liver failure, simple laboratory indices do not reliably distinguish Wilson's disease from viral infection or drug toxicity 1
- Relatively modest aminotransferase elevations in acute liver failure often lead to underestimating disease severity 1
Treatment Principles
Lifelong treatment is mandatory and must never be discontinued, as interruption risks intractable hepatic decompensation or acute liver failure. 5, 7
Treatment Objectives
The two primary objectives are:
- Minimize dietary copper intake to <1-2 mg/day by excluding chocolate, nuts, shellfish, mushrooms, liver, molasses, broccoli, and copper-enriched cereals 7
- Promote excretion and detoxification of excess tissue copper using chelating agents or zinc 7
- Distilled or demineralized water should be used if drinking water contains >0.1 mg/L copper 7
Initial Treatment for Symptomatic Patients
Initial treatment with chelating agents is standard for symptomatic patients, with trientine preferred when D-penicillamine causes adverse reactions. 5, 7, 8
D-Penicillamine
- Produces marked neurologic improvement, fading of Kayser-Fleischer rings, and gradual amelioration of hepatic dysfunction and psychiatric disturbances 7
- Noticeable improvement may not occur for 1-3 months 7
- Neurologic symptoms occasionally worsen during initiation; despite this, the drug should not be withdrawn 7
- Temporary interruption carries increased risk of sensitivity reaction upon resumption 7
- If neurologic symptoms worsen for a month after initiation, several short courses of 2,3-dimercaprol (BAL) while continuing penicillamine may be considered 7
Trientine
- Effective alternative for patients intolerant of D-penicillamine 5, 8
- Dosage varies from 450-2,400 mg/day, with average optimal response between 1,000-2,000 mg/day 8
- In 41 patients intolerant of penicillamine, 34 improved, 4 had no change, and 1 deteriorated 8
- Previous penicillamine intolerance symptoms disappeared in 8 patients, improved in 4, and remained unchanged in 1 8
- Kayser-Fleischer rings improved significantly during treatment 8
Zinc
- Blocks intestinal absorption of dietary copper and reabsorption of endogenously secreted copper 2
- Induces metallothionein production in enterocytes, which binds copper and prevents serosal transfer 2
- Bound copper is lost in stool following intestinal cell desquamation 2
- Must be separated from food and beverages (except water) by at least one hour 2
- Regimen of 50 mg elemental zinc three times daily is effective in inducing negative copper balance 2
Treatment for Decompensated Cirrhosis
Combination therapy with chelator plus zinc, temporally separated by 5-6 hours, is recommended for decompensated cirrhosis, with zinc 50 mg elemental and trientine 500 mg as standard doses. 5
Treatment for Presymptomatic/Asymptomatic Patients
Treatment prevents disease progression indefinitely in presymptomatic/asymptomatic patients, with zinc preferable for children under age 3 years and either zinc or chelators effective for older individuals. 5, 7
- Symptoms and signs appear to be prevented indefinitely if daily treatment continues 7
- Treatment has been carried out successfully for over 30 years 7
Maintenance Therapy
Maintenance therapy involves transitioning to zinc monotherapy or continuing reduced-dose chelator after 1-5 years of chelation with clinical stability. 5
- Stable patients demonstrate normal aminotransferases and hepatic synthetic function 5
Treatment During Pregnancy
Treatment must be maintained throughout pregnancy without interruption, as discontinuation has resulted in acute liver failure, with zinc dosage continued unchanged and chelator dosage reduced by 25-50%. 5
Liver Transplantation
Liver transplantation is the only effective life-saving option for acute liver failure and should be pursued immediately, with one-year survival rate of 79-87% and excellent long-term survival thereafter. 5, 9
- Transplantation corrects the underlying metabolic defect 9
- Also indicated for complications of cirrhosis 4
Family Screening
All first-degree relatives must be screened, as presymptomatic treatment prevents disease progression. 5
Screening should include:
- History and physical examination 5
- Serum ceruloplasmin and copper 5
- Liver function tests 5
- Slit-lamp examination 5
- ATP7B haplotype analysis or mutation testing 5
Monitoring
Clinical measures are used to determine whether patients remain stable, including assessment of aminotransferases and hepatic synthetic function. 5, 2
- Serial recording of brain-stem-evoked responses can monitor improvement 3
- Symptoms and MRI abnormalities may be fully reversible on treatment 3
Prognosis
Clinical experience suggests life is prolonged with appropriate copper restriction and chelation therapy. 7