BASICS

DESCRIPTION

• Wilson’s disease (WD) is an autosomal recessive defect in cellular copper transport characterized by dramatic build-up of intracellular hepatic copper with subsequent hepatic, neurologic, and other systemic abnormalities.

• Also called: Copper storage disease, hepatolenticular degeneration

EPIDEMIOLOGY

• Manifests as liver disease in children, peaking at ages 10–13 years

• Manifests as neuropsychiatric illness in young adults aged 19–20 years

• Males and females affected equally in all ethnic groups.

Incidence

The gene frequency is 0.56% with a carrier frequency of 1 in 90 (see Genetics section).

Prevalence

Approximately 1 case in 30,000 in most populations

RISK FACTORS

Genetics

• Inherited as an autosomal recessive trait

• Genetic defect localized to chromosome 13, which codes for the ATP7B protein (1).

– Can be affected by mutations at many different sites

– Mediates copper transport by sequestering copper into vesicles, which undergo exocytosis across the plasma membrane.

• Normal variations in the PRNP gene modify the course of WD.

– PRNP gene codes for prion protein, which is involved in copper transport.

– Normal variation in the PRNP gene may delay the age of onset of WD or affect clinical manifestations.

GENERAL PREVENTION

Genetic counseling

PATHOPHYSIOLOGY

• Impaired transport of copper from the liver into bile leads to excess copper accumulation in the liver.

• Excess copper may act as a prooxidant.

– Promotes free radical formation

– Progressive hepatic damage manifests as asymptomatic liver function test (LFT) abnormality, chronic hepatitis, portal hypertension, acute liver failure, and eventual cirrhosis.

• Once cirrhosis occurs, free copper leaks into the bloodstream.

– Accumulates in and damages other tissues

– Neuropsychiatric, hematologic, renal, and other organ system disease manifestations

• Incorporation of copper into apoceruloplasmin to form ceruloplasmin is also impaired, accounting for the decreased serum ceruloplasmin.

ETIOLOGY

See Genetics section.

DIAGNOSIS

HISTORY

• Clumsiness

• Difficulty speaking

• Involuntary shaking

• Drooling

• Personality changes

• Depression

• Easy bruising

• Fatigue

• Nausea

• Joint pain

• Impotence

• Night blindness

• Family history of WD

PHYSICAL EXAM

• Signs of acute or chronic liver failure and portal hypertension

– Yellowing of the skin and eyes (jaundice)

– Hepatomegaly

– Swelling of arms and legs

• Neurologic symptoms

– Tremor

– Ataxia

– Parkinsonism

– Dystonia

– Cerebellar and pyramidal signs

– Impairment of vertical eye movements, in particular vertical pursuits, more often than vertical optokinetic nystagmus and vertical saccades (2)

• Kayser–Fleischer ring

– Brownish or gray–green rings that represent fine pigmented granular deposits of copper in Descemet’s membrane in the cornea close to the limbus

– Formation begins first at superior pole, then the inferior pole, and ultimately circumferentially

• Renal dysfunction

– Kidney stones

– Fanconi syndrome (proximal tubular dysfunction) causes abnormal number of amino acids excreted in the urine (aminoaciduria).

DIAGNOSTIC TESTS & INTERPRETATION

Lab

• Liver enzymes: mildly to moderately elevated, often with aspartate aminotransferase (AST) > alanine aminotransferase (ALT)

• Blood ceruloplasmin

– An extremely low serum ceruloplasmin level (<5 mg/dL) is strong evidence for the diagnosis.

– A serum ceruloplasmin concentration<20 mg/dL in a patient who also has Kayser–Fleischer rings is diagnostic (1).

– Serum ceruloplasmin alone has a low positive predictive value, only 6% in one study (3)

– Low serum ceruloplasmin levels also found in asymptomatic WD heterozygotes, marked renal or enteric protein loss, end-stage liver disease of any cause, and other rare disease of copper deficiency

– Normal ceruloplasmin does not rule out WD

Can be elevated in the presence of acute liver inflammation, pregnancy, and estrogen supplementation

• Basal 24-h urinary excretion of copper

– 24-h urinary copper excretion of >100 μg is typical in symptomatic patients (normal <40 μg/day).

– Penicillamine challenge useful in symptomatic children if urinary copper excretion is <100 μg/24 h

– Values of >1,600 μg copper/24 h following the administration of 500 mg of d-penicillamine are found in WD (4).

• Serum copper concentration

– Nonceruloplasmin-bound copper levels are greater than 25 μg/dL in the majority of untreated patients with WD (normal<15 μg/dL).

– Values may be influenced by a variety of conditions; therefore, the sensitivity, specificity, and positive predictive value have not been well-established.

• Slit lamp exam

– Kayser–Fleischer rings, dependent upon type of presentation (1)

– Present in 50–60% of patients who present with isolated hepatic involvement

– Present in 98% of patients who present with neurologic involvement

– Absence of Kayser–Fleischer rings does not exclude the diagnosis.

– Not absolutely specific for WD; reported in other chronic cholestatic diseases.

– Sunflower cataracts, representing copper deposits in the lens

– Rarely, optic neuritis or pallor of the optic disc

Imaging

• Brain CT

– Slit-like, low-attenuation foci involving the basal ganglia, particularly the putamen

– Larger regions of low attenuation in the basal ganglia, thalamus, or dentate nucleus

– Widening of the frontal horns of the lateral ventricles and diffuse cerebral and cerebellar atrophy

• Brain MRI

– More sensitive than CT in detecting early lesions

– Focal abnormalities in the white matter, pons, and deep cerebellar nuclei are typically bilateral with low signal intensity on T1-weighted images, representing cell loss and gliosis.

– Decreased signal intensity in the putamen and other parts of the basal ganglia may represent either copper or iron ferritin deposition.

Diagnostic Procedures/Other

• Liver biopsy

– Essential for diagnosis in absence of Kayser–Fleischer rings or neurologic abnormalities

– Quantitative copper determination (1)

Levels of more than 250 μg/g of dry weight found even in asymptomatic patients.

Normal hepatic copper concentration (15–55 μg/g) excludes the diagnosis.

• Genetic testing currently limited to screening of family members for an identified mutation detected in the index patient.

Pathological Findings

• Liver biopsy

– Ranges from fatty infiltration to cirrhosis

– May appear similar to chronic active hepatitis

– Histochemical staining of liver specimens for copper is of little diagnostic value.

DIFFERENTIAL DIAGNOSIS

• Hepatitis

– Acute or chronic hepatitis of any etiology, commonly mimicking autoimmune hepatitis

• Neuropsychiatric disorders

TREATMENT

MEDICATION

First Line

• Chelating agents: Remove excess copper from body.

– Penicillamine (Cuprimine, Depen) (5)

– Adult: Initial 1.5–2 g PO qday; Maintenance: 750 mg to 1 g/day PO q.i.d.

– Pediatric: 25 mg/kg PO qday

– Extensive side effects including skin problems, bone marrow suppression, worsening of neurological symptoms, and birth defects.

– Must be administered with pyridoxine 25 mg PO qday

– Trientine (Syprine) 250–500 mg PO t.i.d. (6)

If unable to tolerate penicillamine

Risk of bone marrow suppression and worsening neurologic symptoms

Should be administered with zinc

Second Line

• Zinc acetate (150–300 mg PO qday) prevents your body from absorbing copper from the food.

– Approved for maintenance after initial chelation therapy

– Drug of choice in presymptomatic, pregnant, and pediatric populations

ADDITIONAL TREATMENT

General Measures

See Diet section

Issues for Referral

Consultation with a hepatologist recommended

SURGERY/OTHER PROCEDURES

• Liver transplantation

– Primarily reserved for treatment of patients with fulminant liver failure or end-stage liver cirrhosis despite chelation therapy

ONGOING CARE

FOLLOW-UP RECOMMENDATIONS

Patient Monitoring

• Weekly for the first 4–6 weeks following initiation of chelation therapy

– Physical examination, 24-h urinary copper excretion assay, CBC, urinalysis, serum-free copper measurement, and renal and LFTs

• Bimonthly evaluations through the first year, followed by yearly examinations thereafter

• Yearly slit lamp examination to document fading of Kayser–Fleischer rings

DIET

• Limit dietary copper intake

– Avoid liver, shellfish (especially lobster), mushrooms, nuts, legumes, and chocolate

– Avoid copper pots, pans, or containers

– Replace well water with purified water if the copper content is greater than 0.2 ppm.

• Avoid alcohol and hepatotoxic drug therapy

PATIENT EDUCATION

• Wilson’s Disease Association

– http://www.wilsonsdisease.org/home.html

PROGNOSIS

• Fatal if not treated in a timely manner

• If treated early, symptomatic recovery is often complete with a normal life expectancy.

• Residual dysarthria and mild dystonia are relatively common in neurological WD.

• Lifelong chelation therapy is necessary.

COMPLICATIONS

• Chronic liver failure and cirrhosis can lead to bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation abnormalities.

• Fulminant liver failure may occur, especially due to medication noncompliance.

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