Wilson Disease

Indications for Testing

Unexplained liver disease in patients <40 years of age
Unexplained neurological disease, especially in concert with liver disease
Kayser-Fleischer rings on ophthalmic exam
Family history of the disease in first-degree relative

Laboratory Testing

Pattern of results consistent with Wilson disease is most useful for diagnosis
- Ceruloplasmin – decreased (<200 mg/L is highly suggestive of disease)
- Serum free copper – increased (>10 μg/dL is suggestive)
- Urine (24 hour) copper – increased (>100 μg/24-hours is considered diagnostic)
- Hepatic function – transaminases may be elevated; however, not useful in diagnosis
- Molecular testing – ATP7B mutation
  - Not recommended in patient's children; close monitoring may be indicated

Histology

Liver biopsy – increased copper concentrations (>250mg/g dry weight is diagnostic)
- Copper content may be less in cirrhotic liver because of uneven distribution of copper in parenchyma

Imaging Studies

MRI is most useful – increased signal intensity in the basal ganglia on T2 weighted images

Differential Diagnosis

Hepatic manifestations
- Viral hepatitis – hepatitis A, B, C or D
- Chronic hepatitis – hepatitis B or C, autoimmune hepatitis
- Chronic cholestasis – primary sclerosing cholangitis, primary biliary cirrhosis
Neurologic manifestations
- Degenerative cerebellar or metabolic diseases
- Demyelinating disease – amyotrophic lateral sclerosis (ALS)
- Metabolic storage disease – Gaucher disease
- Vasculitis – microscopic polyangiitis, Churg-Strauss syndrome, polyarteritis nodosa
- Central nervous system infections – viral, bacterial, parasitic, fungal
- Seizure disorder
- Parkinsons disease
- Transverse myelitis
- Familial chorea
- Early onset Huntington disease
Psychiatric
- Psychoses
- Depression
- Schizophrenia
- Drug abuse

Genetic testing – consider screening for ATPase (ATP7B) genetic mutation
- Negative result does not exclude Wilson disease

If Kayser-Fleischer rings are initially present, rings should break up and disappear with therapy
Measuring serum free copper is useful in monitoring therapy effectiveness
- Aims to reduce into normal concentrations

Wilson disease (also called hepatolenticular degeneration, Westphal-Struempell disease, and Westphal pseudosclerosis) is an autosomal recessive inherited disorder of copper metabolism.

Epidemiology

Incidence – 1/30,000
Age – onset of symptoms <40 years
Sex – M:F, equal

Inheritance

Caused by mutation in the ATP7B gene (located on chromosome 13)
Autosomal recessive transmission
- ~1% of population are carriers

Pathophysiology

Ceruloplasmin, a late acute phase reactant, is the principal copper-containing protein of plasma and is transported into the trans-Golgi network of all cells by copper-transporting ATPases
Disease results from the absence or dysfunction of copper-transporting ATPases
Variant P-type ATPase prevents incorporation of copper into ceruloplasmin, resulting in elevated concentrations of circulating free copper
Excess copper is deposited in the kidneys, liver (causes cirrhosis), eyes (manifests as Kaiser-Fleischer rings) and brain (damages the basal ganglia)
Other conditions that prevent the elimination of copper (eg, biliary obstruction) may also lead to elevated free copper concentrations

Clinical Presentation

Ophthalmic manifestations
- Kayser-Fleischer rings (copper deposit on corneal Descemet membrane)
  - Seen in 50-60% of patients
  - Not specific for Wilson disease – can also be seen in chronic cholestasis
  - Presence does not correlate with severity
Hepatic manifestations – hepatomegaly, fatty liver, hepatitis, cirrhosis
Neurologic manifestations – movement disorders
- Typically develop in the 20s and affect 40-50% of patients
- Dystonia, tremor, incoordination, rigidity, hypomimia
- Bulbar and pseudobulbar palsies with hypokinetic speech and dysphagia
Psychiatric manifestations
- Behavioral disturbances, depression, hallucinations, paranoia
- Frequently occur prior to hepatic and neurologic symptoms
Complications
- Hematologic – hemolytic anemia, thrombocytopenia
- Musculoskeletal – arthritis, osteoporosis
- Renal – nephrolithiasis, aminoaciduria, Fanconi syndrome
- Cardiac – cardiomyopathy, arrhythmias
- Endocrine – hypoparathyroidism, infertility
- Other – gall stones, pancreatitis

Treatment

Goal of therapy is to reduce copper accumulation; prompt diagnosis is crucial because treatment requires 3-6 months for the desired effect
Untreated Wilson disease can be fatal – result of fulminant liver failure and/or brain damage

Tests generally appear in the order most useful for common clinical situations

Test name: Wilson Disease Screening Panel, Serum

ARUP #: 0020598

Methodology: Quantitative Immunoturbidimetric/Quantitative Inductively Coupled Plasma-Mass Spectrometry

Use:

Diagnose conditions of copper overload in symptomatic patients or patients with a family history of Wilson disease

Panel includes serum ceruloplasmin, serum copper and free serum copper

Supports diagnosis of Wilson disease and monitors therapy in patient with Wilson disease

Limitations:

See individual component tests

Ceruloplasmin false positives may reflect malabsorption, aceruloplasminemia, liver insufficiency, heterozygotes for Wilson disease, inflammatory conditions

Test name: Copper, Urine

ARUP #: 0020461

Methodology: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Use:

Supportive test in diagnosis of Wilson disease

Limitations: False positives from hepatocellular necrosis

Test name: Copper, Liver

ARUP #: 0020694

Methodology: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Use:

Supportive test in diagnosis of Wilson disease

Limitations: False positives from alcoholic hepatitis, cholestatic syndromes

Test name: Copper, Serum Free (Direct)

ARUP #: 0020596

Methodology: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Use:

Supportive test in diagnosis of Wilson disease

Monitoring therapy in patient with Wilson disease

Limitations:

Performed with serum ultrafiltrates

Elevated in Wilson disease or other conditions of copper overload

Elevated results should be confirmed with a second specimen to exclude the possibility of external contamination

Test name: Ceruloplasmin

ARUP #: 0050160

Methodology: Quantitative Immunoturbidimetric

Use:

Supportive test in diagnosis of Wilson disease

Limitations:

Positive result may not necessarily indicate Wilson disease because decreased ceruloplasmin levels may also be found in inflammatory conditions

Pregnancy and oral contraceptives increase ceruloplasmin levels

Low ceruloplasmin levels also found in malnutrition, malabsorption, nephrosis, severe liver disease

Test name: Hepatic Function Panel

ARUP #: 0020416

Methodology: Refer to individual components.

Use:

Supportive test in diagnosis of hepatic dysfunction

Panel includes albumin; alkaline phosphatase; aspartate aminotransferase; alanine aminotransferase; bilirubin, direct; protein, total; bilirubin, total

Additional Tests Available

Test name: Copper, Serum

ARUP #: 0020096

Methodology: Quantitative Inductively Coupled Plasma-Mass Spectrometry

Comments:

Test available alone or as part of Wilson disease serum screening panel that also includes serum ceruloplasmin and serum free copper

False positives from infection, inflammation, stress, copper supplementation, oral contraceptives, pregnancy

Pregnancy - concentrations are 2-3 times normal in third trimester

Copper may be lowered by corticosteroids, zinc, malnutrition, malabsorption