Wilson's disease
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Overview
| Wilson's disease Classification and external resources | |
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| ICD-10 | E83.0 |
| ICD-9 | 275.1 |
| OMIM | 277900 |
| DiseasesDB | 14152 |
| MedlinePlus | 000785 |
| eMedicine | med/2413 neuro/570 ped/2441 |
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Wilson's disease or hepatolenticular degeneration is an autosomal recessive hereditary disease, with an incidence of about 1 in 30,000 in most parts of the world and a male preponderance. Its main feature is accumulation of copper in tissues, which manifests itself with neurological symptoms and liver disease. The estimated heterozygous carrier rate is about 1 in 100, meaning that 1 in 100 people are unaffected carriers of this mutation.
Historical Background
The disease bears the name of the British physician Dr Samuel Alexander Kinnier Wilson (1878-1937), a neurologist[1] who described the condition in 1912.[1] Dr J.N. Cumings made the link with copper accumulation in 1948.[1] The first effective chelation agent, penicillamine, was discovered in 1956 by Dr John Walshe.[1] The genetic basis was elucidated in the 1980s and 1990s by several research groups.[1][1]
Epidemiology and Demographics
In Western populations the incidence is around 1 per 30,000, with a carrier rate of 1 in 100. The gene frequency is much higher in Hispanics, especially in Central America, and in El Salvador, the incidence is 1 in 186. In Usulután Department, El Salvador it has been reported that 1 in 7 persons carry the disease.
Wilson's Disease affects approximately one in 30,000 people worldwide. The genetic defect causes excessive copper accumulation in the liver or brain.
Pathophysiology & Etiology
The Wilson disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta but has also been found in the heart, brain, and lung, albeit at much lower levels. The gene codes for a P-type ATPase that transports copper into bile and incorporates it into ceruloplasmin.
The mutant form of ATP7B expressed in people with Wilson's disease inhibits the release of copper into bile. As the excretion of copper from the body is thus impaired, the copper builds up in the liver and injures liver tissue. Eventually, the damage causes the liver to release the copper directly into the bloodstream, which carries the copper throughout the body. The copper buildup leads to damage in the kidneys, brain, and eyes, presumably by generation of reactive oxygen species and binding to neuromelanin[4]. If not treated, Wilson's disease can cause severe brain damage, liver failure, and death.
Copper deposits in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus), result in cell death, producing symptoms akin to Parkinson's disease.
Small amounts of copper are as essential as vitamins. Copper is present in most foods (see Copper Content of Various Foods), and most people have much more copper than they need. Healthy people excrete copper they don't need but Wilson's Disease patients cannot.
Copper begins to accumulate immediately after birth. Excess copper attacks the liver or brain, resulting in hepatitis, psychiatric, or neurologic symptoms.
The first part of the body that copper affects is the liver. In about half of Wilson's Disease patients the liver is the only affected organ. The initial physical changes in the liver are only visible under the microscope. When hepatitis develops, patients are often thought to have infectious hepatitis or infectious mononucleosis when they actually have Wilson's Disease hepatitis.
Genetics
Wilson's Disease is an autosomal recessive disease, which means it is not sex-linked (it occurs equally in men and women). In order to inherit it, both of ones parents must carry a gene that each passes to the affected child. Two abnormal genes are required to have the disease. At least one in 30,000 people of all races and nationalities has the disease.
The responsible gene is located at a precisely known site on chromosome 13. The gene is called ATP7B. Some cases of Wilson's Disease occur due to spontaneous mutations in the gene. Most are transmitted from generation to generation.
Most patients have no family history of Wilson's Disease. People with only one abnormal gene are called carriers. Carriers (heterozygotes) may have mild, but medically insignificant, abnormalities of copper metabolism. Carriers do not become ill and should not be treated.
More than 200 different mutations of ATP7B have been identified thus far. Therefore, it has been difficult to devise a simple genetic screening test for Wilson's Disease. However, in a particular family, if the precise mutation is identified, a genetic diagnosis is possible by haplotype analysis. This requires a blood sample from both the patient and a relative. The samples are compared to each other. Haplotype testing helps to find symptom-free siblingswho have the disease so that they may be treated before they become ill.
Someday a genetic test may help in genetic screening and prenatal diagnosis. However, at this time, there is no available test for these purposes.
What is the Likelihood of Inheriting Wilson's Disease?
One in 100 individuals in the general population carries one abnormal copy of the Wilson's Disease gene. Carriers have one normal and one abnormal gene. All (100%) children of those afflicted with Wilson's Disease receive at least one abnormal copy of the Wilson's Disease gene. One half (50%) of a carrier's children receive at least one abnormal copy of the Wilson's Disease gene.
Siblings of Wilson's Disease patients have a 1 in 4 chance of having the disease. Since both of a siblings' parents are carriers, 1/4 of the siblings' children have the disease, 1/2 are carriers, and 1/4 are disease free with no Wilson's Disease gene.
Children of patients have a 1 in 200 chance of having the disease. A child of a Wilson's Disease patient has a 100% chance of getting one abnormal gene. The patient's spouse has a 1 in 100 chance of carrying the abnormal Wilson's Disease gene and half the time he or she will pass it on.
Grandchildren of patients have a 1 in 400 chance of having the disease. A grandchild of a Wilson's Disease patient has a 50% chance of getting one abnormal gene, since each a patient's child is a carrier. From the other parent, a grandchild has a 1 in 200 chance of getting the gene (1/2 times 1/200, or 1/400).
Nieces and Nephews of patients with siblings who do not have Wilson's Disease have a 1/600 chance of having the disease. Two-thirds of unaffected siblings carry the gene. The risk both parents being carriers is 2/3 times 1/100, or 1 in 150. The risk of each of their children having the disease is 1 in 600 (1/4 times 1/150).
Cousins of Wilson's Disease patients have a 1 in 800 chance of having the disease.Fifty percent of aunts and uncles are carriers. The risk of both parents of a cousin carrying the abnormal gene is 1/2 times 1/100, or 1 in 200. Since 1 in 4 children of two Wilson's Disease patients is afflicted, the overall risk of a cousin of a Wilson's Disease patient being afflicted is 1/4 times 1/200, or 1/800.
All siblings and children of Wilson's Disease patients should be tested for Wilson's Disease. Other relatives who have had symptoms or laboratory tests that indicate liver or neurological disease also should be tested for Wilson's Disease.
People with Wilson's Disease may not have any signs, symptoms, or evidence of illness. However,people with mild or non-apparent Wilson's Disease will become seriously ill and eventually die if they are not treated.
Testing is simple and safe. There are excellent treatments available. Failure to treat Wilson's Disease causes severe disability and eventually death.
Diagnosis
A suppressed level of ceruloplasmin is present in over 80% of patients, and this is commonly performed as a screening test in patients with liver problems. A more accurate measurement is the direct testing for copper levels in a 24h specimen of urine, in the blood or in the sample obtained by liver biopsy. The average concentration of hepatic copper may reach 20 times normal levels, whilst plasma ceruloplasmin levels are typically less than 30% of normal.
An eye exam would detect the Kayser-Fleischer ring, although its absence does not rule out Wilson's and it may be missed on cursory examination. This sign is characterised by brown rings around the cornea in the eye that result from copper deposition in Descemet's membrane of the cornea. Wilson's disease is also associated with sunflower cataracts, brown or green pigmentation of the anterior and posterior lens capsule.
Signs and symptoms
Symptoms usually appear around the ages of 10 to 21 years, but sometimes not until the age of 30, and in rare instances at age 50 and even beyond. Presentation before 5 years of age is extremely rare, despite the biochemical defect being present at birth.
The age of presentation seems to correlate with the organ system involved. About half (40–50%) of patients first present with hepatic symptoms and half (40–50%) with neurologic symptoms. The average age for hepatic symptoms is 10–14 years, compared with 19–22 years for neurologic symptoms. Patients rarely present after age 40.
The main features are liver and neuropsychiatric problems. Chronic active hepatitis, culminating in cirrhosis is the most common hepatic presentation, but some patients present with fulminant liver failure (which is characterised by remarkably low alkaline phosphatase and often high bilirubin levels compared to similar disease states[1]) and a surprisingly rare incidence of hepatocellular carcinoma. Neuropsychiatric phenomena are early dementia, mood disorders or psychosis and signs of asterixis (a flapping tremor of the hands) and parkinsonism (including ataxia, dyskinesia, and rigidity).
Adjunctive features are renal (renal tubular acidosis, kidney stones), ophthalmic (Kayser-Fleischer rings, sunflower cataracts), cardiac (cardiomyopathy, cardiac arrhythmias) and dermal (hidradenitis suppurativa). Hemolysis (anemia due to destruction of red blood cells) is usually present only in severe cases.
Women may have menstrual irregularities, absent periods, infertility, or multiple miscarriages.
Skin
Jaundice may be present.
Eyes
Opthalmalogic slit lamp examination will demonstrate Kayser-Fleischer rings
Abdomen
Abdominal swelling may be present.
Neurologic
Tremors may be present.
Electrolyte and Biomarker Studies
The diagnosis of Wilson's Disease is made by relatively simple tests. The tests can diagnose the disease in both symptomatic patients and people who show no signs of the disease. These tests can include:
Opthalmalogic slit lamp examination for Kayser-Fleischer rings Serum ceruloplasmin test 24-hour urine copper test Liver biopsy for histology and histochemistry and copper quantification Genetic testing, haplotype analysis for siblings and mutation analysis.
It is important to diagnose Wilson's Disease as early as possible, since severe liver damage can occur before there are any signs of the disease. Individuals with Wilson's Disease may falsely appear to be in excellent health. For additional information, refer to the Boston University Medical Campus website at http://www.bumc.bu.edu/ or consult with your physician.
Screening
Testing for Wilson's Disease should be performed in individuals with unexplained, abnormal liver tests.
Treatment
The disease is treated with lifelong use of chelating agents such as D-penicillamine or trientine hydrochloride, drugs that help remove copper from tissue. Patients will also need to take vitamin B6 and follow a low-copper diet, which means avoiding mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.
Taking extra zinc may be helpful in blocking the intestines' absorption of copper. Zinc acetate is an agent utilized to inhibit copper absorption in patients with Wilson's disease. It blocks the intestinal absorption of the metal both from the diet and endogenous secretions. It also acts by producing metallothionein, a protein that binds with copper to prevent its release into the blood, and facilitates elimination via the stool.
Liver transplantation is effective in patients with fulminant Wilson disease that does not respond to the usual treatment. Because the primary defect resides within the liver, transplantation is curative, but as it is only undertaken in severely ill patients the prognosis is still mediocre.
Prognosis
No matter how the disease begins, it is always fatal if it is not diagnosed and treated.
References
Original text is from a public domain source found at: http://www.niddk.nih.gov/health/digest/summary/wilson/wilson.htm
External links
- Wilson's disease association international
- Wilson's disease UK
- Wilson's disease at Who Named It
- Wilson disease at NLM Genetics Home Reference
- Wilson Disease at NIH/UW GeneTests
- Children's Liver Disease Foundation - The only organisation in the UK dedicated to fighting childhood liver disease. The charity provides support to affected families, helps to educate healthcare professionals and the public, and funds vital research
- Wilson Disease Mutation Database
ca:Malaltia de Wilson de:Morbus Wilsonfr:Maladie de Wilson he:מחלת וילסון nl:Ziekte van Wilson ja:肝レンズ核変性症fi:Wilsonin tauti
Acknowledgement and Attribution Regarding Sources of Content
Some of the initial content on this page may be incorporated in part from copyleft sources in the public domain including wikis such as Wikipedia and AskDrWiki. Drug information for patients came from the The National Library of Medicine. Infectious disease information may have come from the Centers for Disease Control (CDC). Differential Diagnoses are drawn from clinicians as well as an amalgamation of 3 sources: 1.The Disease Database; 2. Kahan, Scott, Smith, Ellen G. In A Page: Signs and Symptoms. Malden, Massachusetts: Blackwell Publishing, 2004:3; 3. Sailer, Christian, Wasner, Susanne. Differential Diagnosis Pocket. Hermosa Beach, CA: Borm Bruckmeir Publishing LLC, 2002:7 .
