- aka hepatolenticular
- a neurodegenerative disease of copper metabolism.
recessive inherited condition caused by mutations or deletions of the
ATP7B protein encoded by chromosome subbands 13q14.3-q 21.1.
- inability to export copper from the liver to the bile (can't
incorporate copper into
ceruloplasmin for subsequent
excretion into the bile - this is the only significant pathway for copper
- Copper accumulates in the liver,
brain, kidney, and cornea.
- Copper accumulation in the cytoplasm of hepatocytes results in cellular
necrosis and leakage of copper into the plasma. The excess copper then
collects in extrahepatic tissues, including the basal ganglia and the limbus
of the cornea.
- The mutated gene is found predominantly in liver, kidney, and placenta,
and to a lesser extent, in heart, brain, lung, muscle, and pancreas. Genetic
testing may be helpful in diagnosing a patient's asymptomatic relatives but
has not replaced the traditional laboratory studies because of the large
number of mutations that have been identified (approximately 70).
- Related disorder of copper: Menkes Kinky Hair Syndrome:
- The Menkes and Wilson ATPases utilize common biochemical mechanisms, but
the tissue-specific expression differs.
Frequency: Internationally: Incidence is 1 in 35,000-100,000 live
births, with a gene frequency of 0.56%; the incidence in Sardinia may be higher.
patients are symptomatic, Wilson disease is fatal if untreated. Patients
who present with fulminant liver failure have a mortality rate as high as 70%.
Age: The onset of liver
disease is usually at age 8-16 years.
Neurological symptoms are rare before
age 12 years.
- Liver disease is the most common
initial manifestation in children.
- Older individuals often present with neuropsychiatric symptoms.
- About 40-50% of patients present with liver disease and 35-50% with
neurological or psychiatric symptoms.
rings are almost always present when the patient has neurological symptoms.
- Wilson disease can be divided into 4 stages—presymptomatic, symptomatic,
symptomatic but treated, and maintenance.
- Parkinsonian symptoms - Rigidity, bradykinesia
- Tremor at rest or with action
- Dystonia mainly of the face
- Poor handwriting
- Abnormal eye movements
- Hyperkinetic behavior
- Irritability or anger
- Emotional lability
- Difficulty concentrating
- Abnormal behavior
- Personality changesDepression
- Joint hypermobility
rings are greenish-yellow or brown rings seen at the limbus of the
cornea. They are best seen by
slit-lamp examination and usually progress from just the superior pole to both
the superior and inferior poles and then finally to a full circle.
- Sunflower cataracts are brilliantly multicolored and are visible only by
slit-lamp examination. They do not impair vision.
- Other less common findings may include exotropic strabismus, optic
neuritis or optic disc pallor, or nightblindness.
Other physical findings
- Azure lunulae of the fingernails
No one test is completely reliable; diagnosis depends upon a high index of
suspicion and supporting laboratory abnormalities.
- Low serum copper level (normal 80-160 mcg/dL)
- Low serum ceruloplasmin level, <20 mg/dL (normal 20-60 mcg/dL)
- Increased urinary copper level, >100 mcg/24 h (normal 10-80 mcg/24 h)
- Renal involvement
- Coombs-negative hemolytic anemia
- Abnormal transaminases
- X-ray or dual energy x-ray absorptiometry (DEXA) scan -
- CT of the head
- Hypodensities in the putamen
- MRI of the brain
- High T2 signal in the basal ganglia, thalami, dentate nuclei, and
cerebellar white matter
- Cortical atrophy
- Ventricular enlargement
- Magnetic resonance proton spectroscopy
- Radiolabeled copper plasma clearance test
- Echocardiogram - May show
- Neuropsychological testing - Difficulties with Reitan trail test part B,
which is sensitive for cognitive impairment associated with liver disease
- Cultured cells - Normal or only slight copper accumulation
- Liver biopsy - Reveals increased hepatic copper, as much as 200-3000 mcg/g
dry weight (normal 20-50 mcg/g)
- Slit-lamp examination for Kayser-Fleischer rings (deep copper-colored
rings at the periphery of the cornea) due to deposition of copper in Descemet
- Copper deposition in the basal ganglia
- Opalski cells - Periodic acid-Schiff–positive altered glial cells
- Cavitary degeneration
- Neuronal loss
- Fulminant liver disease can be treated with
plasma exchange and exchange
transfusion as well as
peritoneal dialysis with albumin 1-1.5 g/dL
200 mg/dL. Intravenous
or trientine also can be
given. These patients will need liver transplantation
- Medical therapy for Wilson disease is very controversial, with Walshe
as the initial therapy of choice and Brewer stating that D-penicillamine
should not be used in Wilson disease at all.
- Zinc is the recommended therapy
during pregnancy, as D-penicillamine and trientine are both teratogenic
in animals and D-penicillamine is teratogenic in humans.
- Therapy with tetrathiomolybdate is being studied by Brewer.
- Surgical Care: Liver
transplantation is indicated for patients with acute hepatic insufficiency; it
also can be considered in patients who do not respond to medical therapy.
Whether liver transplantation is indicated in patients with neurological or
psychiatric disease without liver insufficiency is debatable; however, liver
transplantation has been demonstrated to provide neurological and psychiatric
- Diet: Low copper diet, with
1 mg/d initially (0.5 mg/d for children), is recommended. Dietary copper can
be increased to 1-1.5 mg/d once good control is established; however, average
diets usually contain 1 mg/d. Foods
that are high in copper include shellfish, liver, mushrooms, broccoli,
chocolate, and nuts.
- Penicillamine (Cuprimine)
-- Metal chelator used to treat copper poisoning; forms soluble complexes with
metals excreted in urine. Was first used in 1955. Can reverse neurological
deficits, neuroimaging abnormalities, Kayser-Fleischer rings, and sunflower
cataracts. Psychiatric symptoms, aminoaciduria, peptiduria, and hepatic
disease also improve. Monitoring is done with nonceruloplasmin copper or
urinary excretion of copper.
- Improvement usually begins 5-6 months after starting therapy and continues
for about 24 months. The deficits
present at 24 months are likely to be permanent.
- The psychiatric symptoms usually
resolve, and many of the neurological symptoms improve or resolve as well.
- However, patients usually do have
some cirrhosis even if liver function tests are normal. These patients can
have complications related to their cirrhosis, such as portal hypertension,
resulting in leukopenia
- Patients who present with
liver failure have a mortality rate as high as 70%.
- Noncompliance is an important problem. In one study, occasional
noncompliance was reported in 25% of patients and serious problems with
regular noncompliance were found in 10% of patients despite the fact that the
patients in the study received free medication and care, as well as monitoring
of urinary copper every 6 months.
E-medicine: Wilson Disease (Last Updated: June 17, 2004)