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Wilson disease

This is part of Rare diseases.

Diagnosis: Wilson disease

Synonyms: Hepatolenticular degeneration

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Date of publication: 2006-04-10
Version: 1.3

The disease

In Wilson’s disease, excessive amounts of copper accumulate in the body as a result of impaired copper excretion. If the condition is left untreated it causes life-threatening liver failure and brain damage (hepatolenticular degeneration).

The disorder was first described in 1912 by the Scottish neurologist S.A. Kinnier Wilson as a disease mainly affecting young people. He observed that the condition caused loss of motor function as a result of abnormalities in the nerve cell nuclei, located in the midbrain (the basal ganglia). Another manifestation of the disorder was liver disease (cirrhosis). Wilson’s drew the conclusion that some kind of toxin must be the cause of both symptoms. The toxin in question turned out to be copper.

Occurrence

Wilson’s disease is equally distributed among all ethnic groups. The incidence rate given internationally is approximately 30 individuals per million population, and the number of newly diagnosed cases each year is less than 1 per million individuals. The exact number of people with Wilson’s disease in Sweden is not known, but the estimated figure is around 50. The relatively low number is partly explained by the fact that the diagnosis is frequently overlooked.

Cause

The body receives its supply of copper through water and food. Any copper absorbed in excess of metabolic requirements is excreted through bile from the liver into the stool and out of the body. In Wilson’s disease, copper metabolism, including excretion, is impaired and copper accumulates in liver cells and/or leaks out into the bloodstream where it is transported to the brain and other organs.

The cause of Wilson’s disease is an abnormality (a mutation) in a gene known as ATP7B. This gene codes for an enzyme in the liver which is needed for copper transport. Copper reaches organs and tissues mainly through incorporation into ceruloplasmin, a protein circulating in the bloodstream. Copper is also transported from the liver cells into the bile, through which it can pass out of the body. When the enzyme production is impaired owing to the ATP7B mutation, excess copper is deposited in the liver and other organs, notably the brain.

The defective gene associated with Wilson’s disease is located on chromosome 13. Many different gene abnormalities cause the disease and to date approximately 200 mutations in the Wilson’s gene have been identified.

Heredity

Wilson’s disease is a hereditary autosomal recessive disorder. This means that both the parents of a child with the syndrome are healthy carriers of the mutated gene. In each pregnancy where both parents are healthy carriers there is a 25 per cent risk that the child will inherit the disease. In 25 per cent of the cases the child will neither inherit the disease nor be a carrier of the mutated gene. In 50 per cent of the cases the child will inherit one recessive mutant gene and, like the parents, he or she will be a healthy carrier.

Figure. Autosomal recessive inheritance of genetic traits

If one parent is not a carrier, but the other has an inherited autosomal recessive disorder (and thus has two abnormal genes), the children will all be carriers of the defective gene but the condition will not affect them. If an individual with an inherited autosomal recessive disorder has a child with someone who has one copy of the defective gene, there is a 50 per cent risk that the child will develop the condition, while in 50 per cent of the cases the child will be a healthy carrier.

Symptoms

The first manifestations of Wilson’s disease include liver disease and neurological or psychiatric disorders. Each of the symptoms may present individually or in combination and they may vary in severity. For this reason it can be difficult to discover their underlying cause, and the disease is often overlooked in its early stages. Cases in which the disease presented at the age of three or in people in their sixties have been reported. However, the onset of symptoms is usually between the ages of 5 and 40. In the lower ages, the disease often manifests as acute liver disease and anaemia.

When the normal excretion process via the bile into the stool is impaired, copper accumulates in the liver. The symptoms vary markedly, ranging from mild malfunction to chronic liver disease with cirrhosis or jaundice. Copper deposits may also cause acute liver inflammation (hepatitis), a fatal condition.

Copper also accumulates in the brain, causing neurological and psychological symptoms. In many cases, the disease is discovered in adulthood or during the teen years in individuals who have previously shown no signs of being affected. Neurological symptoms may present as rigid muscles, reduced ability to show facial expression, speech and writing problems and walking difficulties. Other signs of the disease include movement disorders, for example tremors, poor motor coordination, involuntary movements, or spasms that resemble epileptic seizures. Excessive salivation is a common problem and many patients also have chewing and swallowing difficulties.

The psychological symptoms include personality changes, attention and memory deficits causing learning disabilities, anxiety disorders and depression. In rare cases psychosis can occur.

Diagnosis

To make a diagnosis, total serum copper (the concentration of copper in the blood) and the level of copper-transporting ceruloplasmin are analysed. The test results usually indicate low levels of these substances in Wilson’s disease, while the level of free serum copper (copper which does not bind to ceruloplasmin) is high. The low ceruloplasmin concentration is explained by the fact that when ceruloplasmin is not able to bind copper as it should, it breaks down much faster than normal, copper-rich ceruloplasmin.

Other signs of the disease are elevated copper concentrations in the urine and in a liver biopsy (a sample of liver tissue). Penicillamin and trien are copper chelators (substances that bind excess copper) that can be administered to the patient in a provocative test. As these substances increase urinary copper excretion in cases of Wilson’s disease, the test may be valuable in establishing the diagnosis. A brownish ring around the cornea of the eye, known as a Kayser-Fleischer ring, is the result of copper deposition in the eye. The ring is usually present in individuals with neurological manifestations of the disease, but is less frequent in those whose symptoms primarily manifest in the liver. The Kayser-Fleischer ring does not affect vision.

In a radiocopper loading test, radioactive copper is administered to the patient and copper serum levels are monitored for a couple of days. The test is a reliable indicator of whether or not the individual has Wilson’s disease, but it is not sensitive enough to diagnose an unaffected carrier.

The most reliable way of confirming the disease is through genetic diagnosis, in which genetic mutations are mapped. In Sweden, genetic diagnostics is available at Uppsala University Hospital. Close relatives (including cousins) should be offered genetic screening for Wilson’s disease and for carrier status.

Treatment/interventions

Wilson’s disease requires life-long medical therapy regardless of age and symptoms. Medical treatment should continue through pregnancy. If medication is discontinued, the symptoms invariably recur (this may take from one month to one year), and if treatment is not resumed, the condition is fatal. Patients who have undergone liver transplantation are an exception.

The treatment comprises administration of copper chelating agents (substances that bind copper) such as penicillamine and trientine. These medications are taken as tablets and increase urinary excretion of copper. At present, these drugs are not approved for sale in Sweden and usage requires permission from the Medical Products Agency. Penicillamin has been in use longest, but it has many serious side effects. The side effects of trientine are much less severe and this substance is increasingly used as the primary treatment for Wilson’s disease. Tetrathiomolybdate is a new alternative, but so far it has only been used in clinical trials. The substance is a powerful copper chelator but its effects in humans have not yet been fully evaluated. Copper chelator treatment usually lasts between 2 and 6 months until the patient’s copper deposit has been excreted.

Zinc is used for long-term maintenance therapy following the withdrawal of chelator treatment. This mineral blocks gastrointestinal absorption of copper, although the effects are very slow. If a person has been diagnosed with Wilson’s disease but is still symptom-free, zinc should be used as the first-line treatment.

Diet management should be part of the treatment. It is recommended that people with Wilson’s disease reduce their intake of foods with high copper content such as liver, chocolate (with the exception of white chocolate), mushrooms, shellfish and nuts, especially at the beginning of treatment. E-vitamin supplements may also be of value.

Treatment results should be monitored regularly by measuring free serum copper concentration and urinary copper excretion in addition to routine blood, liver and urine tests. Medical examinations should be carried out regularly, on an annual basis if the condition is stable and more frequently if the patient fails to comply with the treatment regime or if the medical doses need to be adjusted.

Psychological symptoms can usually be treated with antidepressants, but as a rule professional aid (from a psychologist and a psychiatrist) is also required. Both the initial disease investigation and follow ups should include neuropsychiatric evaluation.

Other treatment measures should be implemented on the basis of individual symptoms. It is important to establish early contact with a paediatric and adolescent treatment centre or a treatment centre for adults. These multidisciplinary centres offer the competence of professionals including physiotherapists, occupational therapists, speech therapists and counsellors. Interventions may include treatment and training, assessment of the need for aids and equipment and home adaptation. All interventions should be planned in collaboration with specialists at the Swedish Knowledge Centre for Wilson’s Disease.

The prognosis depends on factors such as at what stage of the disease the diagnosis was made, what symptoms have presented and their degree of severity before medical treatment. Patients discovered before the onset of symptoms remain symptom-free, provided they undergo life-long medical treatment. Even in cases where the liver is severely affected, the prognosis is good. Liver transplantation is carried out in cases of acute liver failure, in severe cases of cirrhosis or when medical treatment has resulted in serious side effects.

It is difficult to predict the prognosis of neurological and psychological symptoms, and the prospects for recovery vary from case to case. Treatment usually relieves the symptoms, although improvement may be preceded by a worsening of the condition as chelators release copper into the bloodstream. In isolated cases, the decline may be permanent. However, even individuals with severe neurological symptoms may become practically symptom-free.

Many individuals with Wilson’s disease fall ill during their school years, and may miss out on critical years of education. Supplementary adult education may therefore be necessary. Attention difficulties and increased fatigue may cause psychological and social vulnerability, which should be taken into consideration. Work and education should be adapted to the abilities and limitations of the individual.

If the condition is complicated by persistent neurological and/or psychological symptoms, it may be difficult to maintain a full-time job. Special support may be needed in various situations, for example in handling contacts with the social insurance office, the employer, and health care services, especially regarding matters of adapting the home and workplace.

Women with high copper serum levels sometimes have difficulties becoming pregnant and the risk of miscarriage is elevated. In pregnancy, women should be cared for by maternal-foetal medicine specialists in collaboration with a specialist physician and the Swedish Knowledge Centre for Wilson’s Disease. The liver should be examined and the copper level should be measured monthly in order to detect any worsening of the condition. The prescribed dose of penicillamin or trientine should be lowered during pregnancy so that the foetus is not affected by copper deficiency. However, the treatment must not be interrupted as there is a risk that the mother’s health will deteriorate.

Practical advice

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National and regional resources in Sweden

A multidisciplinary knowledge centre specialising in Wilson’s disease has been established at the Uppsala University Hospital centre of internal medicine. It involves physicians, nurses, a physiotherapist, a speech therapist, a social counsellor and a dietician. They cooperate extensively, for e with neurologists, psychiatrists, Uppsala University PET Centre (Positron Emission Tomography), ophthalmologists, neuroradiologists and the hospital pharmacy. The clinic has more than 20 years’ experience of treating children and adults with Wilson’s disease.

DNA sequencing of selected parts of the ATP7B gene is carried out at the Molecular Medicine Laboratory at Uppsala University. This method of diagnostics is an excellent way of confirming the diagnosis when the disease is suspected, for example in cases of acute liver failure or when regular diagnostic tests for Wilson’s disease fail to deliver a consistent answer. Molecular genetic analysis is recommended for patients with Wilson’s disease in order to provide the genetic information necessary to enable accurate family screening.

Resource personnel

Associate Professor Kerstin Westermark, The Medical Products Agency, Box 26, SE-751 03 Uppsala, Sweden. Tel +46 18 17 46 00.

Erik Waldenström, specialist physician, OTM Division, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 00 00.

Courses, exchanges of experience, recreation

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Organizations for the disabled/patient associations

The Swedish Wilson’s Patient Association. Chair: Michael Gunnarsson, address: Råbystigen 50, SE-197 31 Bro, Sweden. Tel +46 8 582 408 40, email: mailto:michael.gunnarsson@swipnet.se. The patient association can be reached by email: Wilson’ss@passagen.se. They also have a website: http://hem.passagen.se/Wilson'ss.

National Association for Patients with Liver Disease, Box 2918, SE-187 29 Täby, Sweden. Email: kansli@rfl-lever.se, www.rfl-lever.se.

Rare Diseases Sweden, Box 1386, SE-172 27 Sundbyberg, Sweden. Tel: +46 8 764 49 99, email: info@sallsyntadiagnoser.se, www.sallsyntadiagnoser.se.
Rare Diseases Sweden is a federation of rare disease organizations, serving the interests of people with rare disorders.

Courses, exchanges of experience for personnel

For information and advice, contact the Unit for Endocrinology and Diabetes Care, OTM Division, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 43 21.

Research and development (R&D)

The team at Uppsala University Hospital has published a study of abnormalities in the basal ganglia in the brain detectable in an MRI scan (magnetic resonance imaging) and research on basal ganglia function measured with various isotopes and PET (positron emission tomography). Research about copper absorption and distribution measured with a copper isotope and PET is carried out in collaboration with the PET Centre at Uppsala University Hospital.

Clinical trials of alternative medications for treating Wilson’s disease are being carried out in collaboration with the hospital pharmacy at Uppsala University Hospital.

The Knowledge Centre for Wilson’s disease at Uppsala University Hospital has studied the main psychosocial factors that affect the life quality of people with the disease. The survey indicated that people with Wilson’s disease may need supplementary education, treatment of psychosocial problems, speech therapy and work training. Motor abnormalities also require treatment and training.

Mutations in the Wilson’s gene in Swedish patients have been analysed. Continued mapping of the mutations and methodological development are being carried out in cooperation with the Department of Genetics and Pathology at Uppsala University.

Information material

An information folder on Wilson’s Disease which summarises the information in this database text is available free of charge from the customer service department of the Swedish National Board of Health and Welfare (in Swedish only, article number 2001-12-135). Address: SE-120 88 Stockholm, Sweden. Tel: +46 75 247 38 80, fax: +46 35 19 75 29, email: publikationsservice@socialstyrelsen.se. Postage will be charged for bulk orders.

A patient information folder (in Swedish) about Wilson’s disease is available from the Unit for Endocrinology and Diabetes Care, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. Tel +46 18 611 00 00.

Literature

Ala A, Schilsky ML. Inherited metabolic liver disease. Curr Opin Gastroenterol 2004; 20: 198-207.

Dahlman T, Hartvig P, Löfholm M, Lööf L, Westermark K. Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). Q J Med 1995; 88: 609-616.

Olsson C, Waldenström E, Westermark K, Landegren U, Syvänen A-C. Determination of the frequencies of ten allelic variants of the Wilson’s disease gene (ATP7B), in pooled DNA samples. Eur J Hum Genet 2000; 8: 933-938.

Portala K, Westermark K, von Knorring L, Ekselius L. Psychopathology in treated Wilson’s disease determined by means of CPRS expert and self ratings. Acta Psychiatr Scand 2000; 101: 104-109.

Portala K, Levander S, Westermark K, Ekselius L, von Knorring L. Pattern of neuropsychological deficits in patients with treated Wilson’s disease. Eur Arch Psychiatry Clin Neurosci 2001; 251: 262-268.

Portala K, Westermark K, Ekselius L, Broman JE. Sleep in patients with treated Wilson’s disease: a questionnaire study. Nord J Psychiatry 2002; 56: 291-297.

Roberts EA, Schilsky ML. AASLD Practice Guidelines. A Practice Guideline on Wilson’s Disease. Hepatology 2003; 37: 1475-1492.

Thuomas KÅ, Aquilonius SM, Bergström K, Westermark K. Magnetic resonance imaging (MRI) of the brain in Wilson’s disease. Neuroradiology 1993; 35: 134-141.

Waldenström E, Lagerkvist A, Dahlman T, Westermark K, Landegren U. Efficient detection of mutations in Wilson’s disease by manifold sequencing. Genomics 1996; 37: 303-309.

Westermark K, Tedroff J, Thuomas KÅ, Hartvig P, Långström B, Andersson Y, Hörnfeldt K, Aquilonius SM. Neurological Wilson’s disease studied with magnetic resonance imaging and with positron emission tomography using dopaminergic markers. Mov Dis 1995; 10: 596-603.

Database references

OMIM - Online Mendelian Inheritance in Man
Internet: www.ncbi.nlm.nih.gov/omim
search: Wilson disease

GeneReviews (University of Washington). Internet: www.genetests.org (select GeneReviews)
search: Wilson disease

Document information

The Swedish Information Centre for Rare Diseases, produced and edited this information material.

The medical expert who wrote the first draft of the information material is Associate Professor Kerstin Westermark, The Medical Products Agency, Uppsala, Sweden.

The relevant organisations for the disabled/patient associations have been given the opportunity to comment on the content of the text.

The expert group on rare diseases of the Swedish National Board of Health and Welfare approved the material prior to publication.

Date of publication: 2006-04-10
Version: 1.3
Publication date of the original Swedish version: 2006-04-10

For enquiries contact The Swedish Information Centre for Rare Diseases, The Sahlgrenska Academy at the University of Gothenburg, Box 400, SE-405 30 Gothenburg, Sweden, tel: +46 31 786 55 90,
email: ovanligadiagnoser@gu.se.

 

About the database

This knowledge database provides information on rare diseases and conditions. The information is not intended to be a substitute for professional medical care, nor is it intended to be used as a basis for diagnosis or treatment.