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.
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.
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 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.
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.
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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.
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.
Wilson's Disease Association. 〈http://www.medhelp.org/wda/wil.htm〉.
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.
Hunt, Katherine; Frey, Rebecca. "Wilson Disease." Gale Encyclopedia of Medicine, 3rd ed.. 2006. Encyclopedia.com. (June 29, 2016). http://www.encyclopedia.com/doc/1G2-3451601754.html
Hunt, Katherine; Frey, Rebecca. "Wilson Disease." Gale Encyclopedia of Medicine, 3rd ed.. 2006. Retrieved June 29, 2016 from Encyclopedia.com: http://www.encyclopedia.com/doc/1G2-3451601754.html
Wilson disease (WD) is an inherited disorder of copper metabolism, transmitted as an autosomal recessive trait. This type of inheritance means unaffected parents who each carry the WD gene have a 25% risk in each pregnancy of having an affected child. The disorder is caused by a defective copper-binding protein found primarily in the liver, which leads to excess copper circulating through the bloodstream. Over time, the copper is deposited and increased to toxic levels in various body tissues, especially the liver, brain, kidney, and cornea of the eye. Left untreated, WD is invariably fatal.
In 1912, Dr. Samuel Kinnear Wilson described a disorder he called "progressive lenticular degeneration." He noted the familial nature of the condition, and also that it was likely to be caused by a toxin affecting the liver. The toxin was later discovered to be excess copper. Another,
little-used name for the disorder is "hepatolenticular degeneration" (degeneration of the liver and lens), which omits the contribution of neurological symptoms.
The classic triad of signs for WD includes lenticular degeneration, cirrhosis of the liver, and neuropsychiatric symptoms. Errors in a specific gene produce a defective copper-binding protein in the liver, which results in an inability to excrete excess copper. While some copper is necessary for normal metabolic processes in the body, too much can be toxic. The disease is present at birth, but symptoms typically do not show until years later. WD is progressive because the underlying cause cannot be corrected. Effective treatments are available, but without treatment, people with WD will eventually die of liver failure.
WD has an incidence of about one in 30,000, which means one in 90 individuals is a silent carrier of the WD gene. There seems to be no specific ethnic group or race that has a higher frequency of the disease. Only a man and woman who are both silent carriers of the WD gene can have a child with the condition. Unlike a disease with dominant inheritance, which usually implies a definite family history, WD only rarely has occurred in a previous family member.
Causes and symptoms
WD is caused by errors in a gene located on chromosome 13, which produces a protein named ATP7B. Errors in the ATP7B gene produce a protein with decreased ability to bind copper. Unused copper is then absorbed back into the bloodstream where it is transported to other organs. A person who is a carrier of WD has one normally functioning copy of the ATP7B gene, and this produces enough functional protein to rid the body of excess copper.
A little more than half of all patients with WD first show symptoms of hepatitis. In addition, those who have liver-related symptoms first, do so at a younger age than do those who first present with neuropsychiatric symptoms—15 years and 25 years on average, respectively. However, the symptoms and their severity are quite variable, and the diagnosis of WD has been made in children as young as three years old, and in adults in their 60s.
Neurological symptoms are primarily the result of copper's toxic effects in the basal ganglia, a portion of the brain that controls some of the subconscious aspects of voluntary movement such as accessory movements and inhibiting tremor. These symptoms include:
- Dystonia. Prolonged muscular contractions that may cause twisting (torsion) of body parts, repetitive movements, and increased muscular tone.
- Dysarthria. Difficulty in articulating words, sometimes accompanied by drooling.
- Dysphagia. Difficulty swallowing.
- Pseudosclerosis. Symptoms similar to multiple sclerosis.
While the diagnosis of WD may be suspected on clinical grounds, it can only be confirmed using laboratory tests. An easily detectable physical sign is the presence of Kayser-Fleisher rings in the eye, which are bluish rings around the iris, caused by copper deposition in the cornea.
The easiest biochemical test is measurement of ceruloplasmin, a blood protein that is nearly always decreased in patients with WD. While low levels of ceruloplasmin are highly suggestive, a liver biopsy to detect excess copper levels is much more accurate. Testing for mutations in the ATP7B gene is nearly definitive, but the large number of mutations catalogued in the gene means that only certain individuals may benefit from testing. A consultation with a genetics professional is always recommended.
A gastroenterologist will treat and monitor liver disease, while a neurologist and psychiatrist (or neuropsychiatrist) should evaluate and treat neuropsychiatric symptoms. Since many individuals achieve remission of their neurologic symptoms once treatment is started, neuropsychiatric consultations may only be short term. If necessary, periodic consultations with a geneticist can provide updated information on genetic testing.
Treatment of WD revolves around the process of copper chelation. A chelating agent binds to excess copper in the bloodstream so that it can be excreted from the body. Penicillamine is the most effective and commonly used medication, but about 20% of all patients suffer serious side effects, which may include joint pain , blood disorders, fever, an increase in neurologic symptoms, and systemic lupus erythematosus.
Trientine and zinc salts given orally are somewhat less effective, but have fewer side effects than penicillamine. In addition, zinc salts may take several months to have any noticeable effect. A diet low in copper will also have some preventive effect. Finally, for those patients in advanced stages of liver disease, liver transplantation may be the only method of averting liver failure and death.
Recovery and rehabilitation
The earlier in the course of the disorder that treatment is started, the more beneficial the effects will be. For some individuals, liver function may return to near normal, and often dramatic improvements in the neuropsychiatric symptoms can be seen shortly after beginning treatment. For others who have gone untreated for longer periods, or who have a more severe form of the disease, only modest improvements may be seen. Treatment must be lifelong.
A newer copper chelating agent currently being investigated is tetrathiomolybdate. The hope is that it will prove to have fewer side effects than penicillamine, yet be more effective than Trientine. Possible suppression of bone marrow function may yet be a risk for some patients.
For those who begin treatment early in the progression of the disorder, or even before symptoms are noted, the prognosis is excellent, as long as the patients comply with the treatment regimen. For others, the prognosis may be more difficult to predict, but nearly every patient with WD sees at least some improvement once treatment is begun. For those who go untreated, the prognosis is very poor.
The rarity of WD, combined with its diverse and varied symptoms that can mimic other conditions, makes it difficult to diagnose. This is of special concern because it is a progressive fatal condition; yet it can be easily and effectively treated if caught early. The autosomal recessive nature of the condition means that there is almost never a previous family history (other than a diagnosed sibling) to alert anyone to the risk. Because the diagnosis is easily established by measuring serum ceruloplasmin levels, with subsequent liver biopsy for copper levels, anyone contracting hepatitis or cirrhosis with no obvious cause, with or without neuropsychiatric symptoms, should be tested for WD.
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Wilson's Disease Association. 4 Navaho Drive, Brookfield, CT 06804-3124. (800) 399-0266; Fax: (203) 775-9666. <http://www.wilsondisease.org>.
National Center for the Study of Wilson's Disease. 432 West 58th Street, Suite 614, New York, NY 10019. (212) 523-8717; Fax: (212) 523-8708.
Scott J. Polzin, MS, CGC
Polzin, Scott. "Wilson Disease." Gale Encyclopedia of Neurological Disorders. 2005. Encyclopedia.com. (June 29, 2016). http://www.encyclopedia.com/doc/1G2-3435200381.html
Polzin, Scott. "Wilson Disease." Gale Encyclopedia of Neurological Disorders. 2005. Retrieved June 29, 2016 from Encyclopedia.com: http://www.encyclopedia.com/doc/1G2-3435200381.html