Wilson disease


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Wilson Disease

 

Definition

Wilson disease, or WD, is a rare inherited disorder that causes excess copper to accumulate in the body. It is also known as hepatolenticular degeneration. Steadily increasing amounts of copper circulating in the blood are deposited primarily in the brain, liver, kidneys, and the cornea of the eyes. WD is fatal if it is not recognized and treated. It is named for an American neurologist, Samuel A. K. Wilson, who first described it in 1912.

Description

Under normal conditions, copper that finds its way into the body through the diet is processed within the liver. This processed form of copper is then passed into the gallbladder, along with the other components of bile (a fluid produced by the liver, which enters the small intestine in order to help in digestive processes). When the gallbladder empties its contents into the first part of the small intestine (duodenum), the copper in the bile enters and passes through the intestine with the waste products of digestion. In healthy individuals, copper is then passed out of the body in stool.
In Wilson disease, copper does not pass from the liver into the bile, but rather begins to accumulate within the liver. As copper levels rise in the liver, the damaged organ begins to allow copper to flow into the bloodstream, where it circulates. Copper is then deposited throughout the body, building up primarily in the kidneys, the brain and nervous system, and the eyes. Wilson disease, then, is a disorder of copper poisoning occurring from birth.
Wilson disease affects approximately one in 30,000 to one in 100,000 individuals and can affect people from many different populations. Approximately one in 90 individuals are carriers of the gene for Wilson disease.

Causes and symptoms

Wilson disease is inherited in an autosomal recessive manner. Autosomal recessive refers to the pattern of inheritance where each parent carries a gene for the disease on one of his or her chromosome pairs. When each parent passes on the chromosome with the gene for Wilson disease, the child will be affected with the disease. Both males and females can be affected with Wilson disease. If an individual is a carrier of the Wilson disease gene they do not have any symptoms of this disease. In order to be affected, an individual must inherit two copies of the gene, one from each parent. Many cases of Wilson disease may not be inherited but occur as a spontaneous mutation in the gene.
The gene for Wilson disease is located on chromosome number 13. The name of the gene is called ATP7B and is thought to be involved in transporting copper. As of 2004, over 200 different mutations of this gene have been identified, making diagnosis by genetic testing difficult.
Symptoms typically present between the ages of three and 60, with age 17 considered to be the average age a diagnosis is made. About half of all patients experience their first symptoms in the liver. The illness causes swelling and tenderness of the liver, sometimes with fever, mimicking more common disorders, such as viral hepatitis and infectious mononucleosis. Abnormal levels of circulating liver enzymes reveal that the liver is being seriously damaged. This form of damage is referred to as fatty degeneration. Without medical intervention, the liver damage will progress to actual cirrhosis. An often-fatal manifestation of liver disease is called fulminant hepatitis. This extremely severe inflammation of the liver (hepatitis) results in jaundice, fluid leaking into the abdomen, low protein circulating in the blood, abnormalities of the blood clotting system, swelling of the brain, and anemia due to the abnormal destruction of red blood cells.
Neurological symptoms are the first to occur in half of all patients due to copper accumulation in the brain and nervous system. The average age of onset for neurological symptoms is 21. These symptoms include tremors of the hands, uncontrollable movements of the limbs, stiffness, drooling, difficulty swallowing, difficulty talking, and headache. There is no change in patient's intelligence.
About one third of all patients with Wilson disease have a variety of psychiatric symptoms as the first signs of the disease. These symptoms include inability to cope, depression, irritability, increased anger, and inappropriate behavior. Often times patients have trouble completing tasks at work or in school.
Other symptoms that can affect patients with Wilson disease, and may occur before or after a diagnosis has been made include joint disorders, symptoms of arthritis and skeletal problems such as osteoporosis. Patients have occasionally been affected with kidney stones, abnormal handling of glucose in their body and women have menstrual cycle irregularities including stopping their regular cycle temporarily.

Diagnosis

The diagnosis of Wilson disease can be performed relatively easily through several different tests; however, because Wilson disease is so rare, diagnosis is often unfortunately delayed. The tests used to diagnose Wilson disease can be performed on patients who have and who have not already shown symptoms of the disease. It is extremely important to make a diagnosis as soon as possible since liver damage can occur before there are any signs of the disease.
An easy way to diagnose Wilson disease is to measure the amount of a glycoprotein found in the blood called ceruloplasmin. Low levels of ceruloplasmin can diagnose the disease in about 80% of affected patients. This procedure is not as effective for women taking birth control pills, pregnant women, or infants younger than six months of age.
A second test involving an eye examination to detect a characteristic ring of copper deposited in a membrane of the cornea (referred to as Kayser-Fleischer rings)is very easy to perform and is very useful in diagnosing patients who have already exhibited symptoms. This test is not as effective in persons without symptoms. This diagnostic test cannot be used by itself to make a diagnosis because some patients with liver disease but not Wilson disease will test positive.
A third test for diagnosing Wilson disease involves measuring the amount of copper in the liver. This can be accomplished by sampling a portion of the liver, called a biopsy. This is one of the most effective ways in which to diagnose Wilson disease, however the procedure itself is more difficult to perform than the others.
Other tests are also useful, for example measuring the amount of copper passed into the urine daily (high in Wilson disease). Another lab test measures the ability of a patient's ceruloplasmin to bind with a form of copper (decreased in Wilson disease). And finally, as discussed under genetic profile, some patients can be diagnosed through a DNA test to determine whether or not they carry two genes for Wilson disease. This test does not always prove to be useful in certain patients and is of most use when used to test the brothers and sisters of affected patients.
Molecular genetic testing is not particularly valuable in diagnosing WD because of the large number of possible gene mutations.

Treatment

Treatment involves life-long administration of either D-penicillamine (Cuprimine, Depen) or trientine hydrochloride (Syprine). Both of these drugs remove copper deposits throughout the body by binding to the copper which then leaves the body in the urine. This type of treatment is called chelation therapy. Zinc acetate (Galzin) and a low copper diet are other ways in which to treat Wilson disease.
Penicillamine has a number of serious side effects:
  • joint pain
  • neurological problems
  • systemic lupus erythematosus
  • decreased production of all blood elements
  • interference with clotting
  • allergic reactions
Careful monitoring is necessary. When patients have side effects from penicillamine, the dose can sometimes be lowered to an effective level that causes fewer difficulties. Alternatively, steroid medications may be required to reduce certain sensitivity reactions. Trientine has fewer potential side effects, but must still be carefully monitored.
Treatment with zinc acetate is also an effective way to remove excess copper from the body. Zinc is a metal that works to block copper absorption and bind copper in the intestinal cells until it is all released into the stool approximately one week later. The benefit of treatment with zinc is there are no toxic side effects however the zinc is a slower acting agent than the other drugs. It takes four to eight months for the zinc to be effective in reducing the overall amount of copper in the body.
Finally, patients with Wilson disease are encouraged to follow a diet low in copper, with an average copper intake of 1.0 mg/day. Foods to be avoided for the high levels of copper include liver and shellfish. Patients are also instructed to monitor their drinking water for excess levels of copper and drink distilled water instead.
Patients may be given a liver transplant in the event of liver failure as a complication of WD. Liver transplantation has been reported to have a relatively favorable outcome, in some cases decreasing the patient's neurologic symptoms.

Prognosis

Without treatment, Wilson disease is always fatal. With treatment, symptoms may continue to worsen for the first six to eight weeks. After this time, definite improvement should begin to be seen. However, it may take several years (two to five) of treatment to reach maximal benefit to the brain and liver. Even then, many patients are not returned to their original level of functioning. Patients with Wilson disease need to maintain some sort of anticopper treatment for the rest of their lives in order to prevent copper levels from rising in the body. Interruptions in treatment can result in a relapse of the disease which is not reversible, and can ultimately lead to death.

Resources

Books

Beers, Mark H., MD, and Robert Berkow, MD., editors. "Mineral Deficiency and Toxicity." In The Merck Manual of Diagnosis and Therapy. Whitehouse Station, NJ: Merck Research Laboratories, 2004.

Periodicals

Carter, Beth A., MD. "Wilson Disease." eMedicine June 17, 2004. http://www.emedicine.com/ped/topic2441.htm.
Daniel, K. G., R. H. Harbach, W. C. Guida, and Q. P. Dou. "Copper Storage Diseases: Menkes, Wilsons, and Cancer." Frontiers in Bioscience 9 (September 1, 2004): 2652-2662.
Georghe, L., I. Popescu, S. Iacob, et al. "Wilson's Disease: A Challenge of Diagnosis. The 5-Year Experience of a Tertiary Centre." Romanian Journal of Gastroenterology 13 (September 2004): 179-185.
Gow, P.J., et al. "Diagnosis of Wilson's Disease: AnExperience Over Three Decades." Gut 46 (March 2000): 415-419.
Robertson, W.M. "Wilson's Disease." Archives of Neurology 57, no. 2 (February 2000): 276-277.
Velez-Pardo, C., M. J. Rio, S. Moreno, et al. "New Mutation (T1232P) of the ATP-7B Gene Associated with Neurologic and Neuropsychiatric Dominance Onset of Wilson's Disease in Three Unrelated Colombian Kindred." Neuroscience Letters 367 (September 9, 2004): 360-364.

Organizations

American Liver Foundation. 1425 Pompton Ave., Cedar Grove, NJ 07009. (800) 223-0179. http://www.liverfoundation.org.
National Organization for Rare Disorders (NORD). 55 Kenosia Avenue, P. O. Box 1968, Danbury, CT 06813-1968. (203) 744-0100. Fax: (203) 798-2291. http://www.rarediseases.org.
Wilson's Disease Association. 4 Navaho Dr., Brookfield, CT 06804. (800) 399-0266.

Other

Wilson's Disease Association. http://www.medhelp.org/wda/wil.htm.

Key terms

Anemia — A blood condition in which the level of hemoglobin or the number of red blood cells falls below normal values. Common symptoms include paleness, fatigue, and shortness of breath.
Bile — A substance produced by the liver, and concentrated and stored in the gallbladder. Bile contains a number of different substances, including bile salts, cholesterol, and bilirubin.
Biopsy — The surgical removal and microscopic examination of living tissue for diagnostic purposes.
Cell — The smallest living units of the body which group together to form tissues and help the body perform specific functions.
Ceruloplasmin — A protein circulating in the bloodstream that binds with copper and transports it.
Chelation therapy — Amethod of removing copper or other heavy metals from the body by giving medications that bind to the metal and allow it to be excreted.
Chromosome — A microscopic thread-like structure found within each cell of the body and consists of a complex of proteins and DNA. Humans have 46 chromosomes arranged into 23 pairs. Changes in either the total number of chromosomes or their shape and size (structure) may lead to physical or mental abnormalities.
Cirrhosis — A chronic degenerative disease of the liver, in which normal cells are replaced by fibrous tissue. Cirrhosis is a major risk factor for the later development of liver cancer.
Deoxyribonucleic acid (DNA) — The genetic material in cells that holds the inherited instructions for growth, development, and cellular functioning.
Gallbladder — A small, pear-shaped organ in the upper right hand corner of the abdomen. It is connected by a series of ducts (tube-like channels) to the liver, pancreas, and duodenum (first part of the small intestine). The gallbladder receives bile from the liver, and concentrates and stores it. After a meal, bile is squeezed out of the gallbladder into the intestine, where it aids in digestion of food.
Gene — A building block of inheritance, which contains the instructions for the production of a particular protein, and is made up of a molecular sequence found on a section of DNA. Each gene is found on a precise location on a chromosome.
Glucose — One of the two simple sugars, together with galactose, that makes up the protein, lactose, found in milk. Glucose is the form of sugar that is usable by the body to generate energy.
Hepatitis — A viral disease characterized by inflammation of the liver cells (hepatocytes). People infected with hepatitis B or hepatitis C virus are at an increased risk for developing liver cancer.
Jaundice — Yellowing of the skin or eyes due to excess of bilirubin in the blood.
Toxic — Poisoinous.

Wil·son dis·ease

(wil'sŏn), [MIM*277900]
1. A disorder of copper metabolism, characterized by liver cirrhosis, basal ganglia degeneration, neurologic manifestations, and deposition of green or golden brown pigmentation in the periphery of the cornea. The plasma levels of copper and ceruloplasmin are decreased; urinary excretion of copper is increased; and the amounts of copper in the liver, brain, kidneys, and lenticular nucleus are unusually high whereas cytochrome oxidase is reduced. Autosomal recessive inheritance caused by mutation in the copper-transporting ATPase gene (ATP7B) on chromosome 13q.
See also: Kayser-Fleischer ring. Synonym(s): hepatolenticular degeneration
2. Synonym(s): exfoliative dermatitis

Wilson disease

(wĭl′sən) or

Wilson's disease

(-sənz)
n.
A rare genetic disease caused by a defect in copper metabolism, resulting in the accumulation of copper in the liver, brain, kidneys, and cornea and causing neurological symptoms and liver disease.

Wil·son dis·ease

(wil'sŏn di-zēz')
1. A disorder of copper metabolism characterized by cirrhosis, basal ganglia degeneration, neurologic manifestations, and deposition of green or golden-brown pigment in the periphery of the cornea; the plasma levels of copper and ceruloplasmin are decreased, urinary excretion of copper is increased, and the amounts of copper in the liver, brain, kidneys, and lenticular nucleus are unusually high, while cytochrome oxidase is reduced; autosomal recessive inheritance caused by mutation in the copper-transporting ATPase gene (ATP7B) on chromosome 13q.
Synonym(s): hepatolenticular degeneration (2) , Westphal-Strümpell disease.
[S.A.K. Wilson]

Wilson,

Samuel Alexander Kinnier, U.S.-born English neurologist, 1878-1937.
Kinnier Wilson disease - Synonym(s): Wilson disease (1)
Wilson disease - (1) disorder characterized by cirrhosis, degeneration in the basal ganglia of the brain, and deposition of green pigment in the periphery of the cornea. Synonym(s): Kinnier Wilson disease; Strümpell-Westphal disease; Westphal disease; Westphal pseudosclerosis; Westphal-Strümpell pseudosclerosis; Wilson syndrome - (2) generalized exfoliation with scaling of the skin and usually with erythema. Synonym(s): exfoliative dermatitis.
Wilson syndrome - Synonym(s): Wilson disease

Wil·son dis·ease

(wil'sŏn di-zēz') [MIM*277900]
Disorder of copper metabolism, characterized by cirrhosis, basal ganglia degeneration, neurologic manifestations, and deposition of green or golden brown pigmentation in the periphery of the cornea.
[S.A.K. Wilson]

Patient discussion about Wilson disease

Q. Hi this is Wilson; I have a daughter, who is 5. She has frequent nose bleeds when she is behaving badly. Hi this is Bell; I have a daughter, who is 5. She has frequent nose bleeds when she is behaving badly. She has been screened by her school for ADHD and I haven’t had a chance to consult a doctor for her screening and exam for ADHD. I thought that her nose bleeds cause due to her behavior? I need help.

A. I don’t have an idea about this. But I think that you should first discuss these issues with your doctor. Also mention to the doctor if she has any problems with sleeping, like only sleeping 6 hours a night. Try with occupational Therapists which help children and adults with small motor issues like handwriting and also with sensory issues like learning how to calm down. Early intervention is always best.

More discussions about Wilson disease
References in periodicals archive ?
Relationship between oxidative stress and antioxidant systems in the liver of patients with Wilson disease: hepatic manifestation in Wilson disease as a consequence of augmented oxidative stress.
We are very excited to be involved in the WTX101-201 study, the first clinical trial to evaluate a new therapy for Wilson Disease in Europe for more than a decade," said Karl-Heinz Weiss, MD, Associate Professor, Liver Cancer Center, University of Heidelberg.
Measurement of blood holoceruloplasmin by EIA using a mouse monoclonal antibody directed to holoceruloplasmin: implication for mass screening of Wilson disease.
Top 5 Companies in Late Stage Wilson Disease Products
We are delighted to proceed with this important clinical study in Wilson Disease patients as a next step in the development program for WTX101," said David Clark, MD, Chief Medical Officer at Wilson Therapeutics.
Wilson disease (WD) represents a monogenic disease resulting in copper accumulation within tissues.
Food and Drug Administration for the development of WTX101 (bis-choline tetrathiomolybdate), a novel de-coppering agent under evaluation as a treatment for Wilson Disease.
Wilson disease (WD)[4] is an autosomal recessive disorder caused by defects in the copper-transporting P-type ATPase gene (ATP7B)[5] resulting in accumulation of copper in the liver and the brain (1, 2).
Other causes of acute liver failure not induced by acetaminophen overdose include hepatitis B disease, autoimmune hepatitis, Wilson disease, fatty liver of pregnancy, and HELLP (hemolysis, elevated liver enzymes, low platelets) syndrome.
Lam and Mak, in a recent article in this journal (1), described the mechanisms leading to allele dropout in the PCR-based diagnosis of Wilson disease (WD) and reported potential solutions to this problem.
Wilson disease (WD) is an autosomal recessive inherited disorder of abnormal copper metabolism related to mutational inactivation of the ATP7B gene.