AUTHOR AND EDITOR INFORMATION
Section 1 of 11  
Author: Beth A Carter, MD, Assistant Professor of Pediatrics, Department of Pediatric Gastroenterology, Hepatology and Nutrition, Texas Children's Hospital and Baylor College of Medicine
Beth A Carter is a member of the following medical societies: American Gastroenterological Association, American Liver Foundation, and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition
Editors: Erawati V Bawle, MD, FAAP, FACMG, Director, Division of Genetic and Metabolic Disorders, Department of Pediatrics, Children's Hospital of Michigan; Professor (Clinician-Educator), Wayne State University School of Medicine; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center; Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System; Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics and Rehabilitation, University of Nebraska Medical Center
Author and Editor Disclosure
Synonyms and related keywords:
Wilson disease, hepatolenticular degeneration, WD, Wilson's disease, ceruloplasmin, copper accumulation, copper metabolism dysfunction, CNS disorder, cirrhosis, liver disease, hepatic disease, Kayser-Fleischer rings, neurologic disorder, copper deposition
Background
Wilson disease (WD) is an inherited copper metabolism dysfunction disease characterized by cirrhosis and CNS findings. Although it is extremely rare in clinical practice, Wilson disease is important because it is fatal if not recognized and treated. Some have speculated that Wilson disease goes undiagnosed in one half of patients with the disease. Often, the diagnosis is not made until adulthood despite manifestations of the disease in childhood. An American neurologist, Samuel Alexander Kinnier Wilson, first described Wilson disease in 1912.1 Wilson characterized the disease as a degenerative CNS disorder associated with cirrhosis.
Pathophysiology
Wilson disease is an autosomal recessive disorder. A gene for Wilson disease has been linked to the long arm of chromosome 13. The defective protein is a p-type adenosine triphosphatase (ATPase) responsible for copper transport. Research suggests that the disease also involves a defect in the copper-binding protein ceruloplasmin at the messenger RNA (mRNA) level. Organ dysfunction in patients with Wilson disease results from inadequate biliary excretion of copper and subsequent copper deposition, most notably in the liver and CNS. In 2004, Stuehler et al reported that basepair changes in the MURR1 gene were associated with an earlier presentation of Wilson disease.2 MURR1 had previously been established to cause canine copper toxicosis in Bedlington terriers.
Frequency
United States
The carrier frequency is 1 per 90 individuals. The prevalence of Wilson disease is 1 per 30,000 individuals.
International
The inbred populations of Sardinia and several Japanese islands have a higher incidence and prevalence of Wilson disease.
Mortality/Morbidity
- Untreated Wilson disease is uniformly fatal.
- Death results from hepatic, renal, or hematologic complications, generally at age 30 years.
- Patients younger than 20 years typically present with hepatic manifestations. The initial findings in adults are primarily neurologic or psychiatric in nature. In 2004, Stapelbroek et al reported that the H1069Q mutation is associated with a late and neurologic presentation.3
Race
Wilson disease is found in every ethnic and geographic population.
Sex
Males and females are affected in equal numbers.
Age
Children younger than 5 years rarely present with symptoms of Wilson disease; however, Wilson disease has been detected in children as young as 3 years and in adults older than 50 years.
History
- Wilson disease may manifest as a clinical illness that resembles acute hepatitis (malaise, anorexia, nausea, jaundice).
- Patients may report CNS signs and symptoms, such as drooling, speech changes, incoordination, tremor, difficulty with fine motor tasks, and gait difficulties.
- Psychiatric manifestations include compulsive behavior, aggression, depression, impulsive behavior, and phobias.
- The patient or parent often reports deterioration in school or job performance. Intellect is unchanged.
Physical
- Gastrointestinal tract: Hepatic insufficiency and cirrhosis may slowly develop and may result in signs of fulminant hepatic failure, including the following:
- Ascites and prominent abdominal veins
- Spider nevi
- Palmar erythema
- Digital clubbing
- Hematemesis
- Jaundice
- Central nervous system
- CNS pathology in patients with Wilson disease results from copper deposition in the basal ganglia. The resulting signs include drooling, dysphagia, dystonia, incoordination, difficulty with fine motor tasks, masklike facies, and gait disturbance.
- Kayser-Fleischer rings consist of copper granules in the stromal layer of the eye. Color changes are visible only in the Descemet membrane and are typically described as a golden brown, brownish green, bronze, or tannish green color seen in the limbic area of the eye. No visual impairments are associated with the color changes, which may be detected with the naked eye, although slit-lamp examination is mandatory for confirmation. If neurologic symptoms of Wilson disease are present, Kayser-Fleischer rings are always found. The rings may also be seen when only hepatic manifestations of Wilson disease are present, but this scenario is less common. The rings fade and disappear with appropriate therapy.
- Renal system
- The product of the Wilson disease gene is expressed in renal tissue, but whether the renal symptoms are primary or secondary to release of copper from the liver is unknown. Renal complications tend to be functional changes unrelated to identifiable histologic findings.
- Rarely, patients with Wilson disease develop renal stones and associated symptoms. Renal stones are precipitated by hypercalciuria and poor urine acidification. Therapy with copper-chelating agents can improve renal function.
- Musculoskeletal system: Skeletal abnormalities in patients with Wilson disease widely vary and include osteoporosis, osteomalacia, rickets, spontaneous fractures, and polyarthritis.
- Heart: Cardiac manifestations, such as rhythm abnormalities and increased autonomic tone, have been described in patients with Wilson disease. Autopsy findings have included hypertrophy, small vessel disease, and focal inflammation.
- Hematologic signs: Patients with Wilson disease exhibit signs of anemia, presumably due to oxidative injury of the cell membrane caused by excess copper.
- Skin: Skin pigmentation and a bluish discoloration at the base of the fingernails (azure lunulae) have been described in patients with Wilson disease.
Causes
- Wilson disease is an autosomal recessive disease.
- Individuals with Wilson disease are homozygous for a copper metabolism gene located on chromosome 13.
- Family history is a definite risk factor.
Anemia, Chronic
Autoimmune Chronic Active Hepatitis
Glycogen-Storage Disease Type 0
Glycogen-Storage Disease Type I
Glycogen-Storage Disease Type II
Glycogen-Storage Disease Type III
Glycogen-Storage Disease Type IV
Glycogen-Storage Disease Type V
Glycogen-Storage Disease Type VI
Glycogen-Storage Disease Type VII
Hepatitis A
Hepatitis B
Hepatitis C
Other Problems to be Considered
Cirrhosis
Multiple sclerosis
Huntington disease
Depression
Antisocial personality disorder
Parkinson disease
Leukodystrophy
CNS vasculitis
Leigh disease
Neurodegenerative disease
a1-antitrypsin deficiency
Hereditary hemochromatosis
Lab Studies
- Typical laboratory findings in patients with Wilson disease include the following:
- Serum ceruloplasmin levels lower than 20 mg/dL
- Low total serum copper levels
- Increased urinary copper excretion (>100 mcg/d)
- The following laboratory findings may be observed in patients with Wilson disease:
- Elevated aminotransferase levels
- Abnormal coagulation test results
- Hemolytic anemia
- Aminoaciduria, glycosuria, uric aciduria, and calciuria
Imaging Studies
- CT scans of the brain in patients with Wilson disease reveal hypodense regions in the basal ganglia (caudate nucleus, putamen, globus pallidus). Other possible findings include ventricular dilatation, brainstem atrophy, and posterior fossa atrophy. The extent of involvement as demonstrated on CT scans does not provide prognostic information.
- Radiography is not uniformly recommended as part of the workup for Wilson disease in children because musculoskeletal abnormalities are rarely identified in the pediatric population.
Other Tests
Prenatal diagnosis based on DNA linkage analysis is currently available (see GeneTests for laboratories that provide genetic testing). The use of genetic testing can provide unequivocal confirmation of Wilson disease. However, because of the large size of the gene, genetic diagnosis can be challenging. In patients in whom Wilson disease is diagnosed, the patient's family members should be biochemically or genetically screened. Wilson disease Monitoring and treatment of patients with asymptomatic Wilson disease is recommended. Linkage and mutational analysis are needed for prenatal diagnosis.
Procedures
Liver biopsy is the criterion standard for the diagnosis of Wilson disease. In the context of the appropriate clinical picture, a hepatic copper content of more than 250 mcg dry weight of the liver confirms the diagnosis. Copper stain test results are often negative early in the disease. Negative copper stain test results of liver biopsy specimens do not exclude the diagnosis because stored copper may be heterogenously distributed.
Histologic Findings
Laboratory findings in a hepatic section from a patient with severe Wilson disease reveals a proliferation of ductal structures, and histologic staining reveals copper deposition.
Medical Care
- Once Wilson disease is diagnosed, treatment is crucial to avoid a fatal outcome.
- Medical treatment consists of various copper-chelating medications.
- Ammonium tetrathiomolybdate forms complexes with ingested copper and forms complexes with copper and albumin in the blood. The use of ammonium tetrathiomolybdate is currently under investigation for the reduction of initial copper levels in patients with Wilson disease.
Surgical Care
Orthotopic liver transplantation is indicated in patients with Wilson disease with fulminant hepatic failure or disease that is worsening despite chelation therapy.
Consultations
- Neurologist
- Gastroenterologist
- Ophthalmologist
- Geneticist
- Nutritionist
- Surgeon (for transplantation, if indicated)
Diet
Dietary copper intake should be restricted. Copper-containing foods include animal liver or kidneys, shellfish, chocolate, peas, unprocessed wheat, and dried beans.
Timely treatment with copper chelators is essential in patients with Wilson disease to decrease the likelihood of disease progression. Initiating chelation therapy in asymptomatic patients can prevent the deleterious effects of copper on the liver and CNS.
Other medications used to treat Wilson disease include anticholinergics, baclofen, GABA antagonists, and levodopa to treat parkinsonism and dystonia symptoms; antiepileptics to treat seizures; and neuroleptics to treat psychiatric symptoms. In addition, protein restriction, lactulose, or both are used to treat hepatic encephalopathy.
Drug Category: Chelating agents
These agents inhibit toxins by reacting with them to form a less active or inactive complex.
| Drug Name | Penicillamine (Cuprimine, Depen) |
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| Description | Sulfur-containing degradation product of the antibiotic penicillin. Forms a soluble complex with copper that can be excreted by the kidney. |
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| Adult Dose | 250 mg PO qid 1 h ac or 2 h pc |
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| Pediatric Dose | 20 mg/kg/d PO divided qid 1 h ac or 2 h pc; not to exceed 1 g/d |
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| Contraindications | Documented hypersensitivity; renal insufficiency; previous penicillamine-related aplastic anemia or agranulocytosis |
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| Interactions | Increases effects of immunosuppressants, phenylbutazone, and antimalarials; decreases digoxin effects; effects may decrease with coadministration of zinc salts, antacids, and iron |
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| Pregnancy | D - Unsafe in pregnancy
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| Precautions | Cross-allergenicity between penicillamine and penicillin is not universal, so may be cautiously administered to patients who are sensitive to penicillin; adverse reactions include fever, rash, leukopenia, lymphadenopathy, and thrombocytopenia (as many as 20% of patients); loss of gustatory sense and proteinuria rarely occur; serious but rare adverse effects include nephrotic syndrome and autoimmune dysfunction; respiratory symptoms, tinnitus, arthralgia, thyroiditis, optic neuritis, and nausea/vomiting have been reported; may interfere with vitamin B-6 metabolism (administer pyridoxine); if cesarean delivery or surgical procedure is anticipated, decrease dose because penicillamine may interfere with wound healing |
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| Drug Name | Trientine (Syprine) |
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| Description | Effective oral chelator used to induce cupriuresis. Useful in patients unable to tolerate penicillamine. |
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| Adult Dose | 1-1.5 g/d PO divided bid/qid 1 h ac or 2 h pc; not to exceed 2 g/d in divided doses |
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| Pediatric Dose | <12 years: 20 mg/kg PO divided bid/qid 1 h ac or 2 h pc; not to exceed 1.5 g/d
>12 years: Administer as in adults |
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| Contraindications | Documented hypersensitivity; biliary cirrhosis; rheumatoid arthritis; cystinuria |
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| Interactions | Effects decrease with iron or other mineral supplements |
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| Pregnancy | C - Safety for use during pregnancy has not been established.
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| Precautions | Contact dermatitis and iron deficiency anemia are the most common adverse effects; fever, epigastric pain, thrombocytopenia, and respiratory symptoms have been reported; separate administration of trientine and iron by at least 2 h to avoid interaction |
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| Drug Name | Zinc acetate (Galzin) |
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| Description | Zinc salts induce intestinal metallothionein, which binds copper and prevents its passage into the blood stream. Use zinc as maintenance treatment in patients with Wilson disease who were treated initially with a copper chelator. |
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| Adult Dose | 50 mg (as elemental) PO tid 1 h ac or 2 h pc |
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| Pediatric Dose | 25 mg (as elemental) PO tid 1 h ac or 2 h pc |
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| Contraindications | Documented hypersensitivity |
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| Interactions | May impair absorption of tetracyclines and fluoroquinolones |
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| Pregnancy | A - Safe in pregnancy
|
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| Precautions | Do not use as initial treatment in Wilson disease because of length of time necessary before copper uptake is blocked; monitor effects via signs and symptoms of Wilson disease and 24-h urine copper levels; continuation of breastfeeding not recommended secondary to zinc-induced copper deficiency in infants; 24-h urine zinc levels can be used to measure compliance |
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Further Outpatient Care
- Follow-up care
- Once the diagnosis of Wilson disease is established, testing of urinary copper excretion is appropriate during treatment.
- Other laboratory tests used to monitor patients include liver function tests and measurement of serum ceruloplasmin and serum copper levels.
- Expect liver function test results to return to reference range within the first year of therapy.
- Periodic ophthalmologic examinations are recommended to document the disappearance of Kayser-Fleischer rings with therapy.
Deterrence/Prevention
- Consider referring families for genetic counseling.
- An index for Wilson disease that is based on serum bilirubin levels, international normalized ratio, aspartate aminotransferase levels, and WBC count has been described. It may be beneficial in predicting mortality without liver transplantation in patients with Wilson disease.
Complications
- Complications include progressively worsening CNS changes, dysarthria, drooling, dysphagia, and personality changes.
- Hepatic failure is possible.
- Renal and hematologic complications are possible.
Prognosis
- Wilson disease is uniformly fatal if left untreated.
- The prognosis depends on the extent of disease at the time of treatment onset. If treatment is timely, normal life expectancy can be achieved.
- The prognosis is best in asymptomatic siblings in whom Wilson disease has been identified using biochemical or genetic analyses and who have received treatment.
- A poor prognosis (ie, rapid fulminant hepatic failure) has been reported in patients who discontinue chelation therapy.
- A relatively favorable outcome has been reported after liver transplant, with reported decrease in neurologic symptoms. Continued chelation therapy was not necessarily required posttransplantation.
Patient Education
- The Wilson's Disease Association is a source of information (1-800-399-0266).
- Offer genetic counseling to patients who have questions about future offspring or the possibility that asymptomatic relatives may have Wilson disease (see GeneTests for available testing laboratories).
- For excellent patient education resources, visit eMedicine's Liver, Gallbladder, and Pancreas Center and Hepatitis Center. Also, see eMedicine's patient education article, Cirrhosis.
- In June 2004, the EuroWilson project was started with the goal of creating a database of information on newly diagnosed cases of Wilson disease and to design randomized trials for this condition.
Medical/Legal Pitfalls
- Consider and exclude Wilson disease in any child who presents with evidence of liver disease.
- The hepatic presentation of Wilson disease is more common in children. The neurologic presentation is more common in adults.
- The classic Wilson disease triad of hepatic disease, neurologic manifestations, and Kayser-Fleischer rings is rare in everyday practice.
| Media file 1:
CT scan in a 15-year-old adolescent boy who presented with CNS findings consistent with Wilson disease. CT scan reveals hypodense regions in the basal ganglia (caudate nucleus, putamen, globus pallidus). Differential diagnoses based on this image alone included leukodystrophy, vasculitis, and, less likely, infection. Ventricular enlargement and posterior fossa atrophy may also be seen on brain CT scans in a patient with Wilson disease. The extent of involvement as depicted on CT scans does not provide prognostic information. |
 |  View Full Size Image | |
Media type: CT
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Wilson Disease excerpt Article Last Updated: Jun 12, 2007
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