Wilson Disease

• aka hepatolenticular degeneration
• a neurodegenerative disease of copper metabolism.
• autosomal 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 removal)
• 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.

Mortality/Morbidity: Once 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.

History:

• 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.
• Kayser-Fleischer 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.

Physical:

Neurological signs

• Parkinsonian symptoms - Rigidity, bradykinesia
• Dysarthria
• Tremor at rest or with action
• Dystonia mainly of the face
• Dysdiadochokinesia
• Poor handwriting
• Incoordination
• Abnormal eye movements
   

Psychiatric signs

• Hyperkinetic behavior
• Irritability or anger
• Emotional lability
• Psychosis
• Mania
• Difficulty concentrating
• Abnormal behavior
• Personality changesDepression
• Schizophrenia

Skeletal abnormalities

• Osteoporosis
• Osteomalacia
• Chondrocalcinosis
• Osteoarthritis
• Joint hypermobility

Ophthalmic findings

• Kayser-Fleischer 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
• Arthropathy

Lab Studies:

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
  • Hypercalciuria and nephrocalcinosis
  • Secondary Fanconi Syndrome
• Hypoparathyroidism
• Coombs-negative hemolytic anemia
• Abnormal transaminases

Imaging Studies:

• X-ray or dual energy x-ray absorptiometry (DEXA) scan - Osteoporosis
• CT of the head
  • Hypodensities in the putamen
  • Atrophy
• 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 cardiomyopathy
• 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

Procedures:

• 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 membrane

Histologic Findings:

• Copper deposition in the basal ganglia
• Opalski cells - Periodic acid-Schiff–positive altered glial cells
• Cavitary degeneration
• Gliosis
• Neuronal loss

Treatment

• Fulminant liver disease can be treated with plasma exchange and exchange transfusion as well as peritoneal dialysis with albumin 1-1.5 g/dL and penicillamine 200 mg/dL. Intravenous penicillamine or trientine also can be given. These patients will need liver transplantation
• Medical therapy for Wilson disease is very controversial, with Walshe recommending D-penicillamine 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 improvement.
• 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.

Drug info

• 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.

Prognosis:

• 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, varices, and hypersplenism resulting in leukopenia and thrombocytopenia.
• Patients who present with fulminant 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) http://www.emedicine.com/NEURO/topic570.htm