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Wilson Disease

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis

Updated: Nov 26, 2008

Introduction

Background

Wilson disease, or hepatolenticular degeneration, is a neurodegenerative disease of copper metabolism. In 1912, Wilson first described it as a familial disorder associated with neurologic symptoms and cirrhosis. In 1956, Walshe first treated patients with the chelating agent penicillamine.

Although the animal models are not human equivalents of Wilson disease, they are helpful in studying copper metabolism and potential treatments. The Bedlington terrier has an autosomal recessive inherited disease characterized by copper toxicosis.1 The Bedlington terrier does not develop neurologic symptoms, but its liver pathology is similar to that of Wilson disease. Canine copper toxicosis is caused by a mutation of the MURR1 gene, which is also believed to be essential for copper excretion. The MURR1 gene is downstream of the gene that causes Wilson disease.

The Long Evans Cinnamon (LEC) rat and toxic milk mouse both develop autosomal recessive inherited diseases associated with copper overload. LEC rats are reported to develop neurologic symptoms, though hemolysis and hepatitis are the usual presenting symptoms. However, the liver histologic findings in the LEC rats and toxic milk mice are substantially different from those of Wilson disease.

Tetrathiomolybdate (TM) was initially developed to treat chronic nutritional copper poisoning in sheep and is now used for Wilson disease. The Menkes disease gene (MNK) was cloned in January 1993 and identified as a P-type adenosine triphosphatase (ATPase), which led to the identification of the Wilson disease gene (WND) at the end of 1993.

Pathophysiology

Wilson disease involves loss of the ability to export copper from the liver into bile and to incorporate copper into hepatic ceruloplasmin. As a consequence, copper accumulates in the liver, brain, kidney, and cornea. The gene for Wilson disease encodes a cation-transporting P-type ATPase with 14 domains: 6 copper binding, 4 transmembrane, 1 phosphatase, 1 transduction, 1 phosphorylation, and 1 adenosine triphosphate (ATP) binding. About 24.6% of all mutations involve the ATP-binding domain.

A patient with a mutation causing a deletion of transmembrane domain 8 and entire the C-terminal cytoplasmic tail was reported to have liver disease and Kayser-Fleisher rings without neurologic symptoms. The Menkes and Wilson genes have 55% identity in amino acids. The Menkes and Wilson ATPases use common biochemical mechanisms, but their tissue-specific expression differs. The ATPase affected in Wilson disease, ATP7B, is predominantly in the liver and transports copper in the hepatocyte, allowing for the incorporation of copper into ceruloplasmin and its subsequent excretion into the bile. This is the only important pathway for copper removal.

ATP7B, also known as Wilson disease protein or WNDP, delivers copper to ferroxidase ceruloplasmin in Purkinje neurons. WNDP is active during development and adulthood but seems to be downregulated with age. About 58.2% of mutations in the Wilson disease gene are missense mutations, 27% are small deletions or insertions, 7.4% are splice-site mutations, and 7.4% are nonsense mutations. Of the point mutations in Wilson disease, 58.2% are missense mutations, 7.4% are at the splice site, 7.4% are nonsense and 27% are small insertions and/or deletions. Individuals in the same family who have the same genetic mutation in ATP7B may have different phenotypes.

Accumulation of copper 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. All copper-transporting ATPases have a histidine residue in the large cytoplasmic loop, adjacent to the ATP-binding domain. The histidine residue is essential for function, and it is the most common mutation in Wilson disease. The Wilson protein is synthesized as a single-chain polypeptide and is localized to the trans-Golgi network of cells.

ATP7B transports copper into the secretory pathway of the cell for incorporation into the cuproenzymes and excretion from the cell. An increase in the intracellular copper level causes ATP7B to move to a cytoplasmic vesicular compartment. As the copper is concentrated into vesicles for excretion from the cell, the cytosolic copper concentration decreases, and ATP7B returns to the trans-Golgi network. The movement of ATP7B appears to involve amino acid sequences in its carboxyl terminus. The copper concentration is higher in brains of people with Wilson disease than in other people or animals with diseases of copper overload.

Frequency

International

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

  • After patients become symptomatic, Wilson disease is lethal 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 the age of 8-16 years.
  • Neurologic symptoms are rare before the age of 12 years.

Clinical

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 neurologic or psychiatric symptoms.
  • KF rings are almost always present when the patient has neurologic symptoms.
  • Wilson disease can be divided into 4 stages: presymptomatic, symptomatic, symptomatic but treated, and maintenance.

Physical

  • Neurologic signs
    • Parkinsonian symptoms - Rigidity, bradykinesia
    • Dysarthria
    • Tremor at rest or with action
    • Dystonia mainly of the face
    • Dysdiadochokinesia
    • Poor handwriting
    • Incoordination
    • Abnormal eye movements
    • Respiratory dyskinesia which can present as an unusual cough
    • Polyneuropathy (may be initial manifestation and reversible with treatment)
  • Psychiatric signs
    • Hyperkinetic behavior
    • Irritability or anger
    • Emotional lability
    • Psychosis
    • Mania
    • Difficulty concentrating
    • Abnormal behavior
    • Personality changes
    • Depression
    • Schizophrenia
  • Skeletal abnormalities
    • Osteoporosis
    • Osteomalacia
    • Chondrocalcinosis
    • Osteoarthritis
    • Joint hypermobility
  • Ophthalmic findings
    • KF rings are greenish yellow or brown rings seen at the limbus of the cornea. They are best seen on slitlamp examination and usually progress from just the superior pole to both the superior and inferior poles and then finally to a full circle. They may not be present in children or other individuals without neurologic symptoms.
    • Sunflower cataracts are brilliantly multicolored and visible only by slitlamp examination. They do not impair vision.
    • Other relatively uncommon findings include exotropic strabismus, optic neuritis or pallor of the optic disc, and nightblindness.
  • Other physical findings
    • Azure lunulae of the fingernails
    • Arthropathy

Causes

Wilson disease is an autosomal recessive inherited condition caused by mutations or deletions of the ATP7B protein encoded by chromosome subbands 13q14.3-q 21.1. This gene encodes a 1411–amino acid protein that is a P-type ATPase. The gene is found predominantly in liver, kidney, and placenta but also in the heart, brain, lung, muscle, and pancreas. The most common genetic mutations are single–base pair changes or frame-shift mutations due to small deletions. On occasion, splicing errors are found. Genetic testing may be helpful in diagnosing the disease in a patient's asymptomatic relatives, but it has not replaced the traditional laboratory studies because of the large number (>200) of mutations that have been identified.

About 95% of serum copper is bound to ceruloplasmin. The serum ceruloplasmin level is usually low in Wilson disease, not because copper levels affect the synthesis of apoceruloplasmin but because the half-life of apoceruloplasmin decreases from 4-5 days to 4-5 hours in the absence of copper. The copper in liver cells is not excreted and is thought to cause oxyradical damage.

Differential Diagnoses

Cortical Basal Ganglionic Degeneration
Olivopontocerebellar Atrophy
Essential Tremor
Parkinson-Plus Syndromes
Hallervorden-Spatz Disease
Primary Torsion Dystonia
Multiple Sclerosis
Progressive Supranuclear Palsy
Multiple System Atrophy

Other Problems to Be Considered

Drug-induced parkinsonism

Neuroleptics
Antiemetics - Metoclopramide (Reglan)
Antihypertensives - Verapamil (Calan), methyldopa (Aldomet), reserpine (Serpasil)
Flunarizine
Lovastatin (Mevacor)
Amiodarone
Cytosine arabinoside

Toxin-induced parkinsonism

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
Carbon monoxide poisoning
Cyanide poisoning
Manganese poisoning
Industrial chemical toxicity - Diquat, carbon disulfide, methanol, N -hexane, lacquer thinners

Miscellaneous conditions

Vascular parkinsonism
Structural lesions
Hydrocephalus
Metabolic parkinsonism - Hypothyroidism, hyperthyroidism, hypoparathyroidism
Posttraumatic parkinsonism - Dementia pugilistica
Hemiatrophy hemiparkinsonism
Postencephalitic parkinsonism

Differential diagnosis for pigmented corneal rings

Carotenemia arcus senilis
Chronic active hepatitis
Chronic cholestasis
Chronic jaundice
Cryptogenic cirrhosis
Intraocular foreign body with <85% copper (if >85%, severe suppurative inflammatory reaction usually present)
Multiple myeloma
Primary biliary cirrhosis
Topical copper solution treatment of the eye
Trypanosomiasis

Workup

Laboratory Studies

  • Need for correlation: No one test is completely reliable. The diagnosis depends on a high index of suspicion and supporting laboratory abnormalities.
  • Proposed diagnostic criteria: At the 8th international meeting on Wilson and Menkes disease in Leipzig, Germany in 2001, the following recommendations were made for the diagnosis of Wilson disease: Extrapyramidal symptoms, KF rings, low ceruloplasmin level, and high urinary copper excretion in patients presenting with neurologic symptoms and KF rings, low serum ceruloplasmin level, and high urinary copper excretion in patients presenting with hepatic symptoms.
  • The serum copper level is low (normal, 80-160 mcg/dL).
  • Low serum ceruloplasmin level of <20 mg/dL (normal, 20-60 mcg/dL)
    • The ceruloplasmin level may be normal in patients with active liver disease and in women taking oral contraceptives or during pregnancy.
    • Ceruloplasmin values may also be reduced in a number of other illnesses, including Huntington disease, multiple sclerosis, subacute sclerosing panencephalitis, Hallervorden-Spatz syndrome, and aceruloplasminemia.
  • Increased urinary copper level, >100 mcg/24 hours (normal, 10-80 mcg/24 h)
    • The level may be normal in children and asymptomatic siblings.
    • A repeat collection after oral challenge with D-penicillamine 500 mg at the beginning and 12 hours later can be done.
  • Renal involvement
    • Hypercalciuria and nephrocalcinosis
    • Secondary Fanconi syndrome with renal tubular acidosis and/or aminoaciduria
  • Hypoparathyroidism
  • Coombs-negative hemolytic anemia
  • Abnormal transaminase levels

Imaging Studies

  • Radiography or dual-energy x-ray absorptiometry (DEXA) scan - Osteoporosis
  • CT of the head
    • Hypoattenuations in the putamen
    • Atrophy
  • MRI of the brain
    • High signal in the basal ganglia, thalami, dentate nuclei, and cerebellar white matter on T2-weighted images
    • Cortical atrophy
    • Ventricular enlargement
    • Sinha et al reported reversible central pontine myelinolysis like changes in 10 patients. All had contiguous midbrain involvement with a round, bisected or trisected shape.2
  • Magnetic resonance spectroscopy
    • In 1999, Kraft et al found no statistically significant differences between 12 treated patients (9 with neurologic symptoms) and 12 healthy control subjects in ratios myoinositol/creatine (MI/Cr) and choline-containing compounds/creatinine (Cho/Cr), N -acetyl-aspartate/creatine (NAA/Cr), and lactate/creatine (Glx/Cr) in the parietal gray matter and white matter, as well as the putamen. The authors thought that decreased MI/Cr and Cho/Cr ratios were correlated with hepatic encephalopathy.3
    • In 2005, Lucato et al reported findings in 36 patients compared with 37 healthy control subjects. Individuals with Wilson disease had decreased NAA/Cr ratios in the parieto-occipital white matter, frontal white matter, and basal ganglia. They also found an increased MI/Cr ratio in the basal ganglia.4
  • Tc-99m TRODAT-1 SPECT
    • Wang et al found decreased striatal Tc-99m TRODAT-1 uptake in both symptomatic and asymptomatic patients with Wilson disease in the striatum, especially the posterior putamina.5
    • Wang et al also found that the striatum/cerebellum ratio had a negative correlation with the severity of neurologic symptoms.5
  • Transcranial sonography (TCS) of the brain parenchyma can show lenticular nuclei hyperechogenicity in asymptomatic patients and can be more sensitive than brain MRI.

Other Tests

  • Liver biopsy - Increased hepatic copper levels, as much as 200-3000 mcg/g dry weight (normal, 20-50 mcg/g)
    • This should be measured by mass spectroscopy or atomic absorption spectroscopy.
    • Histochemical copper staining with rhodanine is insensitive (<10%).
    • Patients with other chronic liver disease, especially those with cholestasis may also have elevated copper levels.
    • Because of sampling error, normal copper content does not rule out Wilson disease.
  • Mutation analysis
    • Conformation-sensitive gel electrophoresis can be used to screen members of a family with known Wilson disease.6
    • Allele dropout can occur in PCR analysis with compound heterozygotes when one allele fails to amplify.7,8
    • Genotyping microarray9
  • Echocardiography - May show cardiomyopathy
  • Neuropsychological testing - Difficulties with Reitan trail test part B, which is sensitive for cognitive impairment associated with liver disease
  • Cell culture - Normal or only slight copper accumulation

Procedures

  • Slitlamp examination for KF rings (deep copper–colored rings at the periphery of the cornea) due to deposition of copper in the Descemet membrane.
  • An experienced ophthalmologist should perform the slitlamp examination.

Histologic Findings

  • Brain findings
    • Copper deposition in the basal ganglia
    • Opalski cells - Periodic acid-Schiff–positive altered glial cells
    • Cavitary degeneration
    • Gliosis
    • Neuronal loss
  • Liver findings10
    • Diffuse cytoplasmic copper accumulation seen with special histochemical stains can be associated with macrosteatosis, microsteatosis, and glycogenated nuclei.
    • Periportal inflammation, mononuclear cellular infiltrates, erosion of the limiting plate, lobular necrosis, bridging fibrosis, and Mallory bodies
    • Cirrhosis with micronodular or mixed macronodular-micronodular pattern

Staging

Eisenbach et al11  found that patients with acute liver failure due to Wilson disease had much lower alanine aminotransferase and aspartate aminotransferase levels than patients with acute liver failure due to other causes. Alanine aminotransferase level was less than 100 in Wilson disease but more than 1000 in patients with acute liver failure due to other causes. They also noted lower choline esterase activity and hemoglobin levels, but the urinary copper concentration was much higher in patients with acute liver failure due to Wilson disease. Acute liver failure was defined as new-onset liver disease characterized by coagulopathy [international normalized ratio (INR) ≥1.5] and any grade of hepatic encephalopathy in the absence of any prediagnosed liver disease. Of their 7 patients, 4 did survive without liver transplantation.

Petrasek et al12 found that the Revised Wilson Disease Prognostic Index (RWPI) had a higher accuracy and lower false negative rate than the Wilson Disease Prognostic Index (WPI) or the Model for End-Stage Liver Disease (MELD) Score in predicting response to chelation therapy. All their patients with decompensated chronic Wilson disease improved with chelation therapy with penicillamine initially, although 6 of the 14 patients later required transplantation. They all had a MELD score less than 30, WPI 7 or lower, and RWPI 11 or lower.

In the Petrasek study, fulminant Wilson disease (group 1) was defined as fulminant hepatic failure at the first presentation of Wilson disease, severe coagulopathy (INR >2), and either encephalopathy or hemolytic anemia. Decompensated chronic Wilson disease (group 2) was defined as known chronic liver disease with sudden onset of jaundice with liver synthetic dysfunction with neither encephalopathy nor hemolytic anemia. Of the 21 patients with fulminant liver disease, 4 died after being listed for liver transplantation. The 17 remaining patients received transplants but 5 of those patients also died in the early posttransplant period within 29 days of the transplant.

The survival of 4 patients without liver transplantation in the Eisenbach group may be due to the slightly different criteria with INR 1.5 or greater in Eisenbach's study as compared with the INR of greater than 2 used in Petrasek's study.

Czlonkowska et al13 proposed a novel scale for rating the neurologic symptoms in Wilson disease. The scale consists of 3 points for consciousness, 39 points for a historical review based on the Barthel scale, and 143 points for the neurologic examination. They developed the new scale to integrate the dystonia, ataxia, and parkinsonism that are often seen in combination in patients with Wilson disease.

Treatment

Medical Care

  • Medical therapy for Wilson disease is still controversial.
    • In 1999, Walshe recommended D-penicillamine as the initial therapy of choice14 , and Brewer stated that D-penicillamine should not be used in Wilson disease at all15 .
    • In 2005, Brewer recommended TM with zinc for 8-16 weeks and zinc or trientine if TM is not available.16
    • Although initial use of D-penicillamine can worsen neurologic symptoms, Czlonkowska et al16 did not note any difference in mortality for 164 patients treated with D-penicillamine or zinc sulphate as initial therapy.
    • Pranshanth et al recommend a start-low, go-slow approach if penicillamine is used.
    • Both D-penicillamine and zinc can reverse liver fibrosis.
    • Brewer et al reported a double-blind randomized trial of TM 20 mg tid with meals and 20 mg tid between meals vs 500 mg of trientine hydrochloride bid in 48 patients with a neurologic presentation. All patients also received zinc 50 mg tid in 2006.17
      • Neurologic deterioration occurred in 6 of the 23 patients receiving trientine and 1 of the 25 patients receiving TM.
      • During the 3-year study, 4 of the 6 patients with initial neurologic deterioration who were receiving trientine died.
  • Zinc is the recommended therapy during pregnancy because D-penicillamine and trientine are both teratogenic in animals and because D-penicillamine is teratogenic in humans.
    • Zinc therapy reduces copper accumulation in the LEC rat.
    • In 2005, Carelli reported zinc use with 10-year follow-up in children. Zinc was given to individuals younger than 6 years without an adverse effect on growth. Dosages were 25 mg of elemental zinc bid to age 6 years, 25 mg tid to age 16 years or 125 lb, and 50 mg tid after that.
  • Gene therapy18 : Investigational in animal models. Viral gene transfer provided transient transgene expression that did reverse clinical symptoms.

Surgical Care

Liver transplantation is indicated for patients with acute hepatic insufficiency; it also can be considered in patients whose disease does not respond to medical therapy. Whether liver transplantation is indicated in patients with neurologic or psychiatric disease without liver insufficiency is debatable; however, liver transplantation provides neurologic and psychiatric improvement.

Pal et al reported that left-sided stereotactic thalamotomy reduced severe bilateral postural kinetic tremor of the hands.19

Diet

A low copper diet, with 1 mg/d at first (0.5 mg/d for children), is recommended. Dietary copper intake can be increased to 1-1.5 mg/d after good control is established; however, average diets usually contain 1 mg/d. Foods high in copper content include shellfish, liver, mushrooms, broccoli, chocolate, and nuts.

Medication

The goals of pharmacotherapy are to reduce morbidity and prevent complications.

Chelating agents

These agents were initially developed to prevent intoxication resulting from drug overdose. Dimercaptopropanol (or British anti-Lewisite [BAL]) was the first therapy used in Wilson disease. It has 2 sulfhydryl groups that form a 5-member ring with copper. BAL can cross the blood-brain barrier. It must be administered intramuscularly and is known to cause tachyphylaxis, probably secondary to induction of liver enzymes. Dimercaptopropane sulphonate (Unithiol) is an orally active derivative of BAL. The agents listed below are those most widely used today.


Penicillamine (Cuprimine)

Metal chelator used to treat copper poisoning; forms soluble complexes with metals excreted in urine. First used in 1955. Can reverse neurologic deficits, neuroimaging abnormalities, KF rings, and sunflower cataracts. Psychiatric symptoms, aminoaciduria, peptiduria, and hepatic disease improve. Monitor nonceruloplasmin copper value or urinary excretion of copper.

Dosing

Adult

250 mg PO qid, 500 mg PO bid, or 15-25 mg/kg/d; can be decreased to 10-15 mg/kg/d once patient reaches basal copper excretion of 50-70 mcg/d; must be taken with empty stomach

Pediatric

Not established

Interactions

Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; zinc salts, antacids, and iron may decrease effects

Contraindications

Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Risk of hypersensitivity reaction at start or other adverse effects 20-30% (can be treated with steroids or by lowering dose or temporarily stopping); can suppress bone marrow and proteinuria; other adverse effects are systemic lupus and immune complex nephritis (=5%); other less common adverse effects are Goodpasture syndrome, epidermolysis bullosa, myasthenia gravis, urticaria, connective tissue changes, and altered immune function; may be associated with neurologic deterioration within 2-6 weeks of start (may be permanent [Brewer]); worsening may be due to increased brain copper levels during start or shifts in intraneuronal copper level; in animal studies, damaged collagen and elastin; D-penicillamine teratogenic in humans and animals


Zinc acetate

Schouwink first used in 1961; approved in 1997. In intestinal cells, induces synthesis of metallothionein, which has high affinity for copper and prevents absorption of endogenously secreted and dietary copper. Copper excreted in stool with sloughed intestinal cells.

Monitor compliance and efficacy with 24-hour urinary zinc (should be =2 mg) and copper (should be <125 mcg) levels; can be done q6mo then annually. May also check nonceruloplasmin copper level (plasma copper level - 3X ceruloplasmin level); should be <25.

Acute hepatic copper crisis can occur if patient not at steady state stops taking drug for few weeks. May be treatment of choice for presymptomatic patients; not teratogenic.

Dosing

Adult

37.5 mg PO bid; Brewer recommends 50 mg PO tid as standard dose; Shimizu (1999) recommends 5-7.5 mg/kg/d; must be taken 1 h before or 2 h after meals

Pediatric

<1 year: Not recommended
1-5 years: 25 mg PO bid (recommended by Brewer)
6-16 years: 25 mg PO tid
>16 years: 50 mg PO tid

Interactions

May reduce penicillamine and tetracycline effects

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Main adverse affect is gastric intolerance; patients may have progression of disease for 4-6 mo after starting therapy


Trientine (Syprine)

Tetramine hydrochloride; chelates copper and increases its urinary excretion. May monitor urinary copper excretion or nonceruloplasmin copper level; useful in patients unable to tolerate penicillamine.

Dosing

Adult

250 mg PO qid, 500 mg PO bid, or 40-50 mg/kg/d; should be taken on empty stomach

Pediatric

Not established

Interactions

Iron or other mineral supplements decrease effects

Contraindications

Documented hypersensitivity; biliary cirrhosis; rheumatoid arthritis; cystinuria

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Can cause bone marrow suppression and proteinuria; at start, obtain CBCs weekly; reported to induce neurologic worsening; teratogenic in animals


Ammonium tetrathiomolybdate (TM)

Harper and Walshe first used in 1984. Binds tissue copper, rendering it metabolically inert, and blocks intestinal copper absorption. May monitor by measuring molybdenum and nonceruloplasmin copper levels. When levels equal, all copper in blood complexed. Takes 3-15 d to reach equilibrium. Given with meals, prevents intestinal absorption of copper; given between meals, absorbed into body and forms complex with albumin and copper.

Dosing

Adult

20 mg PO q4h for 8 wk followed by zinc acetate maintenance therapy; improved neurologic function in 53 of 55 patients

Pediatric

Not established

Interactions

None reported

Contraindications

Documented hypersensitivity

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Ammonium TM causes reversible anemia when patients overtreated; copper essential for hemoglobin synthesis and cellular development

Follow-up

Further Inpatient Care

Treatment of fulminant liver disease

  • 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 can also be given.
  • Almost all patients need liver transplantation (see Staging).

Prognosis

  • Improvement usually begins 5-6 months after the start of therapy and continues for about 24 months. The deficits present at 24 months are likely to be permanent.
  • Psychiatric symptoms can resolve, and many neurologic symptoms can improve or resolve as well. However, patients usually have cirrhosis even if liver function is normal. Patients can have complications related to cirrhosis, such as portal hypertension, varices, and hypersplenism resulting in leukopenia and thrombocytopenia.
  • Merle et al20 found that patients presenting with neuropsychiatric symptoms were more likely to have a longer delay to definitive diagnosis (44.4 mo vs 14.4 mo), progression of symptoms despite treatment, and a poorer outcome than patients presenting with hepatic symptoms. Treatment side effects also occurred in 74.4% of their 163 patients. Patients also presented at a younger age with hepatic symptoms (15.5 y vs 20.2 y).
  • Patients who present with fulminant liver failure have a mortality rate as high as 70%.

Patient Education

For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article, Cirrhosis.

Miscellaneous

Special Concerns

  • Noncompliance is an important problem.
  • In 1 study, occasional noncompliance was reported in 25% of patients, and serious problems with regular noncompliance were found in 10% of patients though patients received free medication and care and though urinary copper values were monitored every 6 months.
  • Sinha and Taly21 reported that 44 of 45 patients on zinc and penicillamine maintenance therapy remained stable after penicillamine was discontinued but 1 patient worsened. Mishra et al22 reported 2 cases of disease progression from presymptomatic to symptomatic disease and biochemical abnormalities despite treatment with zinc. The 2 children both responded to penicillamine.
  • Narayan and Kaveer23 reported a 13-year-old child with hypodensity of the white matter of the frontal, parietal, and temporal lobes consistent with demyelination and both generalized atrophy of the cerebral hemispheres and atrophy of the basal ganglia after 4 years of treatment with 750 mg/d penicillamine, which is equivalent to the adult maintenance dose, and 280 mg/d of zinc, which is nearly double the adult maintenance dose. 

    The authors noted that the serum ceruloplasmin was virtually undetectable and the serum copper (16 μg/dL) was much lower than the normal range of 80-120 μg/dL. They thought the CT changes were due to hypocupremia. The child presented at age 9 years with difficulty using hands and ambulating and with slurred speech for 6 months. He did have basal ganglia atrophy on the initial head CT. On follow-up examination, the KF ring was still present on the superior and inferior margins of both corneae and other abnormalities were apparent.
  • Walshe24 reported that in 67 patients seen from 1948-2000, diagnostic failure was the principal cause of death. Multiple other causes of death included poor compliance and the development of malignant disease after 10 years of follow-up.

References

  1. Owen CA Jr, Ludwig J. Inherited copper toxicosis in Bedlington terriers: Wilson's disease (hepatolenticular degeneration). Am J Pathol. Mar 1982;106(3):432-4. [Medline].

  2. Sinha S, Taly AB, Ravishankar S, Prashanth LK, Vasudev MK. Central pontine signal changes in Wilson's disease: distinct MRI morphology and sequential changes with de-coppering therapy. J Neuroimaging. Oct 2007;17(4):286-91. [Medline].

  3. Kraft E, Trenkwalder C, Then Bergh F, Auer DP. Magnetic resonance proton spectroscopy of the brain in Wilson's disease. J Neurol. 246(8):693-9. [Medline].

  4. Lucato LT, Otaduy MC, Barbosa ER, et al. Proton MR spectroscopy in Wilson disease: analysis of 36 cases. AJNR Am J Neuroradiol. May 2005;26(5):1066-71. [Medline].

  5. Wang P, Hu P, Yue DC, Liang H, Xu JH. The clinical value of Tc-99m TRODAT-1 SPECT for evaluating disease severity in young patients with symptomatic and asymptomatic Wilson disease. Clin Nucl Med. Nov 2007;32(11):844-9. [Medline].

  6. Sundaresan S, Eapen CE, Shaji RV, Chandy M, Kurian G, Chandy G. Screening for mutations in ATP7B gene using conformation-sensitive gel electrophoresis in a family with Wilson's disease. Med Sci Monit. Mar 2007;13(3):CS38-40. [Medline].

  7. Lam CW, Mak CM. Allele dropout in PCR-based diagnosis of Wilson disease: mechanisms and solutions. Clin Chem. Mar 2006;52(3):517-20. [Medline].

  8. Gupta A, Nasipuri P, Das SK, Ray K. Simple and effective strategies for detection of allele dropout in PCR-based diagnosis of Wilson disease. Clin Chem. Aug 2006;52(8):1611-2. [Medline].

  9. Gojová L, Jansová E, Külm M, Pouchlá S, Kozák L. Genotyping microarray as a novel approach for the detection of ATP7B gene mutations in patients with Wilson disease. Clin Genet. May 2008;73(5):441-52. [Medline].

  10. Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML. Wilson's disease. Lancet. Feb 3 2007;369(9559):397-408. [Medline].

  11. Eisenbach C, Sieg O, Stremmel W, Encke J, Merle U. Diagnostic criteria for acute liver failure due to Wilson disease. World J Gastroenterol. Mar 21 2007;13(11):1711-4. [Medline].

  12. Petrasek J, Jirsa M, Sperl J, Kozak L, Taimr P, Spicak J, et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. Jan 2007;13(1):55-61. [Medline].

  13. Czlonkowska A, Tarnacka B, Möller JC, Leinweber B, Bandmann O, Woimant F, et al. Unified Wilson's Disease Rating Scale - a proposal for the neurological scoring of Wilson's disease patients. Neurol Neurochir Pol. Jan-Feb 2007;41(1):1-12. [Medline].

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Keywords

Wilson's disease, hepatolenticular degeneration, liver cirrhosis, copper overload, Kayser-Fleischer rings, KF rings, Bedlington terrier, disease of copper metabolism, Long Evans Cinnamon rat, LEC rat, toxic milk mouse, MNK, WND

Contributor Information and Disclosures

Author

Celia H Chang, MD, Associate Health Sciences Clinical Professor, Department of Neurology, University of California at Davis
Celia H Chang, MD is a member of the following medical societies: American Academy of Neurology and Child Neurology Society
Disclosure: Nothing to disclose.

Medical Editor

Christopher Luzzio, MD, Clinical Assistant Professor, Department of Neurology, University of Wisconsin at Madison
Christopher Luzzio, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: Nothing to disclose.

Managing Editor

Nestor Galvez-Jimenez, MD, MSc, MHA, Chairman, Department of Neurology, Program Director, Movement Disorders, Department of Neurology, Division of Medicine, Cleveland Clinic Florida
Nestor Galvez-Jimenez, MD, MSc, MHA is a member of the following medical societies: American Academy of Neurology, American College of Physicians, and Movement Disorders Society
Disclosure: Nothing to disclose.

CME Editor

Matthew J Baker, MD, Consulting Staff, Collier Neurologic Specialists, Naples Community Hospital
Matthew J Baker, MD is a member of the following medical societies: American Academy of Neurology
Disclosure: Nothing to disclose.

Chief Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association
Disclosure: Nothing to disclose.

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