Eve A. Roberts, M.D., FRCPC
Division of Gastroenterology and Nutrition, Department of Pediatrics,
The Hospital for Sick Children and University of Toronto, Toronto, Ontario, Canada
Wilson disease (technical name: hepatolenticular degeneration) is an inherited disorder of copper handling in the liver. Copper is not packaged properly into its carrier protein in the liver, and it is not excreted efficiently into the bile. Consequently, copper accumulates in liver cells. When too much copper is in liver cells, it spills into the blood stream and is deposited in other organs, mainly the brain and the eyes.
Copper is found in many foods. Trace amounts are essential for good health, but too much copper can be toxic. Most people excrete the extra copper that they do not need, but persons with Wilson disease cannot do this adequately.
Wilson disease is named after an eminent neurologist, Kinnear Wilson, who first described the disease in 1912. Although born in the United States, he worked mainly in England. He described progressive neurologic disease in children in the same family, although he observed that some children also had liver disease. The ring of copper deposited in the eye, near the iris, called the Kayser-Fleischer ring, was described only a few years earlier. Copper's role in damaging the liver was confirmed in the late 1940s. The genetic pattern of inheritance (called autosomal recessive) was determined in 1960. The gene that is abnormal in Wilson disease was identified in 1993. The technical name for this gene is ATP7B, but it also is called WND. The gene is located on chromosome 13.
The gene that is abnormal in Wilson disease (ATP7B) is the blueprint for a protein found mainly in liver cells but also in some brain cells and in certain parts of the kidney. In liver cells, this protein uses energy stored in the cell to move copper out of the cell, which is why the protein is called a "copper-transporter." If the gene is abnormal, then the protein is not put together correctly and does not work.
The gene is large, with over 80,000 base pairs organized in 22 coding units. By looking at the patterns in the gene, scientists can predict the features of the protein it makes. The protein has a tail of 6 units to bind copper and a zone to make a hole, or "pore" in a membrane, through which copper moves; it also has the mechanism for capturing cellular energy to fuel the whole process of transporting copper. This gene is complicated. Thus far, approximately 200 different mutations (or abnormal changes) in this gene have been identified.
Autosomal recessive inheritance means that a person must have 2 abnormal versions of the WND gene to get the disease. The change that makes a gene abnormal is called a "mutation." In Wilson disease, some people have 2 copies of the same mutation, but many people with Wilson disease have 1 copy of 2 different mutations. Either way, having 2 abnormal WND genes means a person has Wilson disease. If a person has only 1 abnormal gene, then that person is a carrier of the disease but does not get the disease. The parents of a person with Wilson disease are obliged to be carriers.
Wilson disease is considered to be rare. It occurs worldwide at the rate of 1 per 30,000 population, meaning that the carrier rate is approximately 1 per 90 population, which is a relatively high rate compared to many inherited diseases. Wilson disease is found in all racial groups. In a few places, the rate of Wilson disease is unusually high; for example, in Sardinia off the coast of Italy, the disease rate is approximately 1 per 10,000 population.
Younger patients typically have signs of liver disease, and the liver disease can be highly variable. Many adult patients primarily have neurologic disease, usually with problems relating to movement. These patients usually have signs of liver damage. Some children and teenagers mainly develop neurologic disease. A minority of patients has only psychiatric symptoms. Although copper can be deposited in the eye, it does not disturb eyesight.
Since Wilson disease is genetic, it is with a person from birth. Most people remain asymptomatic for years and do not know that they have Wilson disease. Children as young as 3 years can have severe liver disease from Wilson disease. Some adults develop only neurologic problems due to Wilson disease when they are in their fifth decade. In general, liver problems from Wilson disease become evident in people aged 5 through 40 years. Those persons with neurologic problems from Wilson disease become symptomatic when they are aged 10 through 55 years.
One of the complicated aspects about Wilson disease is that it leads to many different types of liver disease some severe, some not. At an early stage, Wilson disease may cause slight enlargement of the liver, possibly with extra fat in the hepatocytes. At a later stage, the liver becomes scarred or cirrhotic, often without any symptoms of liver disease. Patients with clinically evident liver disease can have an acute illness similar to viral hepatitis or resembling an autoimmune liver injury. Exceptionally, sudden and rapidly progressive liver failure can occur. This usually is accompanied by an abrupt and severe anemia, poor clotting function, changes in mental function (eg, stupor, coma), and renal failure.
Symptoms of Wilson disease affecting the nervous system are extremely variable, but with 2 main patterns. Movement disorders include tremors, involuntary movements, poor coordination, and loss of fine movements. Many patients actually have decreased movement; they get a stiffness of movement, mincing pattern to their gait, and loss of relaxed and spontaneous facial expression. They also may have garbled speech, drooling, and difficulty swallowing. In teenagers, excessive clumsiness, unexplained deterioration in school performance, and change in handwriting from large round letters to small jagged letters warrant consideration of Wilson disease. Personality or mood changes or depression may accompany these symptoms. Seizures are uncommon with Wilson disease. Intellect is normal.
Copper can accumulate in the heart muscle and result in an abnormal heart rhythm. Copper overload in the pancreas can cause pancreatitis. Copper can cause red blood cells to break down (hemolytic anemia), leading to some jaundice. Gallstones also may result. Copper can interfere with various endocrine organs. In particular, women with Wilson disease may have difficulty becoming pregnant or have repeated miscarriages.
Relatively simple blood and urine tests may be enough to determine whether or not a person has Wilson disease. The concentrations of copper and ceruloplasmin in the blood are low. The amount of copper excreted in the urine over 24 hours is higher than normal. Blood tests to determine liver function are performed. A computed tomography (CT) scan or magnetic resonance imaging (MRI) of the brain may be performed. The eyes should be examined carefully with a slit lamp to see if early Kayser-Fleischer rings are present. More complicated tests include sampling a small amount of the liver by a liver biopsy to examine the liver under the microscope and to measure the actual amount of copper in the liver tissue. Genetic testing can be performed with a blood sample to determine gene patterns that go with Wilson disease or to detect specific mutations.
Wilson disease was one of the first liver diseases for which effective, lifesaving treatment was found. Currently, several possible treatments are available for Wilson disease. These treatments are the chelators, penicillamine and trientine, and the metallothionein-inducer, zinc. Other treatments are essentially experimental.
In use since 1956, penicillamine is a treatment for Wilson disease. It binds copper and increases the excretion of copper in the urine. This treatment may increase the amount of the safe storage protein for copper, called metallothionein, in liver cells. Penicillamine has other unrelated actions that include inhibiting the immune response and interfering with the formation of collagen (a protein in fibrous tissues). Although originally identified as a breakdown product of the antibiotic penicillin, this drug currently is manufactured by itself, without involving penicillin. Penicillamine may deplete vitamin B6 (pyridoxine) in the body; therefore, extra vitamin B6 is taken with it.
Penicillamine has been a lifesaving treatment for Wilson disease since it first was discovered, and many specialists still regard it as the first-line treatment for Wilson disease. Although this treatment works for most people, it can have adverse effects, including fever and rash soon after starting the drug, damage to the kidneys causing protein to leak into the urine, problems with the bone marrow so that blood counts drop dangerously low, and complicated damage to numerous organs at the same time (ie, "lupus-like" drug reaction). Some patients who mainly have neurologic problems with Wilson disease get worse neurologically soon after starting penicillamine; this problem is usually, though not always, transient. A patient having any of these adverse effects may need to change to another treatment. The blood count and urinalysis have to be monitored whenever penicillamine is used. Some specialists believe that penicillamine is flawed as a treatment because of the potential for these adverse effects and advocate using other treatments.
Trientine is a very different chemical from penicillamine, but it is also capable of binding copper and of increasing the amount of copper excreted in the urine. This treatment does not have the risk for adverse effects like penicillamine. When trientine is substituted for penicillamine, the adverse effects of penicillamine usually stop. Anemia may develop because this drug also can bind iron, and, rarely, it may cause nausea because of stomach irritation. Trientine is not quite as strong a binder of copper as penicillamine, but, in day-to-day experience, this difference is not important. Zinc, taken in very high doses, removes copper from the body by increasing the amount of metallothionein in the cells lining the intestinal tract. Copper is bound within these cells and lost in the feces as these cells turn over every 3-5 days. Zinc is surprisingly strong and quite specific for eliminating copper from the body. This treatment has few adverse effects, but it can cause stomach irritation (gastritis).
A few other copper-binding agents have been tried and largely discarded from general use because they were unpleasant to take (eg, daily injections) or had unacceptable adverse effects. Some agents are still under development (eg, tetrathiomolybdate), which means that their effectiveness and adverse effects are not yet fully known. The safety and effectiveness of combining treatments also is not fully determined.
Most people can be treated satisfactorily with the currently available treatments (ie, penicillamine, trientine, zinc). Any of these treatments must be used daily for life. If a treatment has to be stopped because it is causing an adverse effect, another treatment must be substituted. Stopping successful treatment altogether inevitably leads to major deterioration. If treatment is started again, it may not work. In most cases, liver transplant then becomes the only effective treatment available.
Most patients have follow-up visits twice a year to ensure that they are generally healthy. Their physician conducts a physical examination and monitors for adverse effects of drug treatment. Blood counts, liver tests, and urinalysis are performed, and the level of copper and ceruloplasmin in the blood is checked. The amount of copper excreted in the urine in 24 hours is checked approximately once a year to ensure that treatment is effective. A follow-up slit lamp examination of the eyes may be performed to see whether the Kayser-Fleischer rings disappear.
Especially in the first year of treatment, foods that have very high concentrations of copper should be avoided. These foods are shellfish, nuts, chocolate, mushrooms, and organ meats (eg, brains, liver). Since the latter do not play an important role in the average North American diet, shellfish, nuts, and chocolate are the foods to target. Advice from a dietitian may be helpful and is mandatory for practicing vegetarians. Well water or water brought into the household through copper pipes should be checked for copper content. In general, municipal water supplies do not have to be checked. A water purifying system may be advisable if the copper content of the water is high.
Copper may damage liver cells and other cells in the body by causing the formation of activated chemical intermediates. Antioxidants, such as vitamin E, may neutralize these chemicals. High doses of vitamin E may be used in addition to a drug to bind copper.
Most patients with Wilson disease can be treated successfully just with medication, and liver transplant is not necessary. A few patients who do not respond to treatment require a liver transplant. The rare patient whose first sign of Wilson disease is acute liver failure requires immediate liver transplantation. Some patients on treatment who have very severe neurologic disease improve if they undergo a liver transplant, but, presently, the use of liver transplantation to treat the neurologic disease remains controversial. Patients who fail to comply with medical therapy may develop overwhelming liver damage, which can be treated adequately only by a liver transplant.
Alcohol can cause damage to liver cells that is similar in some ways to the kind of damage caused by copper; therefore, drinking alcohol is not advised in those persons who have Wilson disease.
If a person has Wilson disease and gets pregnant, what should that person do about medication during the pregnancy?
Although a small risk exists that the medication for Wilson disease will damage the baby, the greatest risk to the baby occurs if the disease is not well controlled during pregnancy. Therefore, taking the medication during pregnancy is important for those women with Wilson disease. Management of the pregnancy by a high-risk obstetrics team may be advisable depending on the severity of the underlying liver disease.
Since Wilson disease is inherited by an autosomal recessive pattern, a person must have 2 abnormal genes to get Wilson disease. This means that if a person with abnormal genes marries a person with normal genes, the children inherit 1 abnormal gene and 1 of the mate's normal genes. The children are carriers of the disease, but they do not have Wilson disease. If a person with normal genes marries a person who is a carrier of Wilson disease (ie, has 1 abnormal gene), then a 50-50 chance exists with each pregnancy that the child will have Wilson disease.
As soon as 1 child in the family is diagnosed with Wilson disease, all brothers and sisters should be tested. Each child has a 1 in 4 chance of being affected with the disease. Initial studies can be limited to a physical examination; blood tests of liver function; the concentration of copper and its carrier protein, ceruloplasmin, in the serum; and a measurement of the amount of copper excreted in the urine over a 24-hour period. If these studies are suggestive of Wilson disease, further studies may be required. Such studies may include a slit lamp examination of the eyes for Kayser-Fleischer rings, a liver biopsy, and CT scan or MRI of the brain. Since patients who begin treatment before they have any symptoms have the best prognosis, performing these studies is important. If the tests are inconclusive, they should be repeated several times, at 6- to 12-month intervals. If genetic testing is available, an excellent alternate approach is to use genetic testing to confirm who is affected and who is not. The genetic findings in the child with Wilson disease and parents can be used to guide the studies in the other children. Although a genetic approach provides the best data, because so many different mutations exist, it may be difficult to identify which mutation(s) are present in an individual family.
Research is aimed at understanding as much as possible about the protein that is coded for by the ATP7B gene. Research is ongoing to identify as many mutations of the ATP7B gene as possible and to understand why Wilson disease is so variable as a clinical disease. Research also is focused on learning exactly how copper damages the liver and other organs so that even safer and more effective treatments for Wilson disease can be found. Because other inherited diseases involving copper overload occur, some researchers are studying the basis of those diseases.
Hepatolenticular degeneration: The scientific name for Wilson disease, without using the name of the physician who discovered it, meaning that the main damage is to the liver and to the lenticular area of the brain Ceruloplasmin: The protein in the blood that carries over 95% of the copper in the blood stream Metallothionein: A storage protein for copper and other metals inside of cells Chelator: Any chemical that binds a metal such as copper Mutation: A change in a gene leading to the abnormal function of the protein for which the gene codes Kayser-Fleischer ring: Deposit of copper in the eye, close to the iris; characteristic of Wilson disease but also found in other conditions with copper overload
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About the Author
Dr. Roberts obtained her medical degree from the Johns Hopkins University School of Medicine and trained in hepatology at The Royal Free Hospital under Professor Dame Sheila Sherlock. She is currently professor of paediatrics, medicine, and pharmacology at the University of Toronto and a hepatologist at the Hospital for Sick Children.
Copyright 2012 Eve A. Roberts, M.D., All Rights Reserved