Wilson's disease is a genetic disorder in which copper builds up in the body. Symptoms are typically related to the brain and liver. Liver related symptoms include vomiting, weakness, fluid build up in the abdomen, swelling of the legs, yellowish skin, and itchiness. Brain related symptoms include tremors, muscle stiffness, trouble speaking, personality changes, anxiety, and seeing or hearing things that others do not.
Wilson's disease is an autosomal recessive condition due to a mutation in the Wilson disease protein (ATP7B) gene. For a person to be affected they must inherit an affected copy of the gene from each parent. Diagnosis may be difficult and often involves a combination of blood tests, urine tests, and a liver biopsy. Genetic testing may be used to screen family members of those affected.
Wilson's disease is typically treated with dietary changes and medication. Dietary changes involve eating a low copper diet and not using copper cookware. Medications used include chelating agents such as trientine and d-penicillamine and zinc supplements. Complications of Wilson's disease can include liver failure, liver cancer, and kidney problems. A liver transplant may be helpful in those in whom other treatments are not effective or if liver failure occurs.
Wilson's disease occurs in about 1 in 30,000 people. Symptoms usually begin between the ages of 5 and 35 years. Males and females are equally affected. It was first described in 1854 by Friedrich Theodor von Frerichs and is named after Samuel Wilson.
Wilson disease (WD) requires lifelong treatment and can be successfully managed with medication therapy and a low-copper diet in most patients. While WD is a very treatable condition, in about 5-10% of patients with WD liver transplantation is needed. These include patients in whom the disease is diagnosed after there's been significant liver damage that cannot respond to medication alone, including some who may have previously had treatable disease but stopped taking their medication and those presenting with acute liver failure due to WD. Although highly unusual, unexplained liver failure can occur in patients even when they've been faithfully taking their medication, often due to the presence of concurrent liver diseases.
When the liver can no longer function adequately, the damaged organ can be surgically removed and replaced with a healthy liver or part of a liver from a donor. In liver transplantation, the new organ may come from a deceased donor or a living donor.
Liver transplantation is a lifesaving treatment option for those WD patients with chronic or sudden liver failure,. There are about 6,000 liver transplants a year in the United States. There have been 570 adults and children with WD who received liver transplants between 1987 and 2008. With transplantation the disease is actually eliminated since the inherited metabolic defect causing WD is in the liver cells of the damaged liver. However, patients who undergo organ transplantation must take multiple medications to prevent rejection of their new organ for the rest of their lives.
Wilson disease (WD) is a highly treatable condition when identified in a timely fashion when there is adequate liver function, and as long as patients faithfully take appropriate medications for life. Treatment works by reducing or eliminating the accumulation of dietary copper or preventing reaccumulation of copper in your body. Copper chelating drugs that include penicillamine and trientine may be prescribed. Therapy with Zinc salts that blockscopper absorption are another option for treatment, but are approved mainly for maintenance therapy or for treating asymptomatic patients. Eating a low-copper diet by limiting or avoiding foods such as chocolate, nuts, shellfish, organ meats, and mushrooms and by attention to copper content in the water is also recommended.
In other cases, WD patients may not respond to any therapeutic options. Some patients, at their time of diagnosis may have advanced liver failure that can't be treated with medication. In rare instances, WD patients who have faithfully taken their medications may experience unexplained liver failure, often due to other causes of liver injury independent of their WD.
While therapy for WD is very effective in halting progression of the disease and sometimes even reversing symptoms, some patients may become non-adherent to their medications and diet. Non-adherence means stopping medication use or not taking it regularly as directed. Studies of various diseases show rates of non-compliance to medication regimens can range from 20-50%. People with WD who never experienced disease symptoms due to early diagnosis or those experiencing side effects from the medications may be more at risk of falling into this category. It's extremely important for those with WD to follow their doctor's treatment recommendations and have regular monitoring of their treatment for life!
In these circumstances, liver transplantation may be the only remaining treatment option.
WD patients with stable liver disease should still undergo routine check-ups and laboratory testing twice a year, and those with abnormal testing more frequently. Blood is drawn and evaluated in a lab to determine how the liver is functioning, and 24 hour urine studies are obtained along with other testing for copper to determine if the treatments are effective. Doctors also check for clinical signs of liver disease and neurological functioning. If either appears abnormal, further tests may be ordered and monitoring becomes more frequent.
When the liver isn't working right, patients will see physical signs that can't be ignored. Jaundice is typically the first or main symptom: the skin will turn pale yellow or orange and the whites of the eyes will also look yellow. In some, there is fluid accumulation and edema (swelling) of the lower extremities and abdominal distension due to ascites can occur. Other symptoms indicating liver failure include:
Loss of appetite and weight loss
Tenderness in upper right side of abdomen
Nausea, vomiting, diarrhea, light-colored stools, darkening color of urine
Poor blood clotting
Confusion, irritability, and mood changes
If you or a family member notices any of the above physical or emotional changes, it's important to see your doctor immediately! Liver failure can advance quickly so symptoms should not be ignored. If laboratory and other diagnostic tests determine the liver is severely damaged and is unlikely to regenerate or heal itself, patients should undergo an evaluation for liver transplantation at a transplant center, and a liver transplant may be recommended.
Your doctor will let you know if it's time to have an evaluation for a liver transplant. The first step is identifying a medical center with a liver transplant program that's close to your home, if possible. Since there are a limited number of organs that are available for transplantation, there is a limited number of centers with medical teams skilled and approved to perform liver transplants. The choice of a center with the capability to perform living donor liver transplant should also be considered as this will help increase the odds of obtaining a timely organ if potential donors are available. Family members who are carriers for WD may also be suitable donors and should not be excluded from consideration on the basis of being a carrier alone.
A transplant evaluation takes several days and may involve being admitted to the hospital. If a child is being evaluated, a parent or guardian should be present during the hospital stay. The evaluatioon involves a number of medical tests including blood tests, heart tests, possible liver biopsy, ultrasound or CT and MRI scans, lung, and kidney function tests.
The evaluation is performed by a variety of specialists on the transplant team. The transplant team includes hepatologists, transplant surgeons, transplant coordinators, nurses, social workers, psychologists and other specialists who may be called in for specialized care. A transplant is a major operation and maintaining the organ in the recipient requires long-term care and follow-up so the transplant team needs to be assured that the patient has appropriate family and emotional support.
The liver is the largest and most complex organ you have in your body. It weighs about three pounds in adults and performs lifesaving functions ranging from the processing of carbohydrates, fats, proteins, and nutrients absorbed from food to making the factors needed to help your blood clot. It breaks down toxic substances in your blood such as drugs and alcohol and is responsible for metabolizing medications. Your liver is an essential organ that you cannot live without!
The majority of liver transplants performed in people with WD have been adults. According to the United Network for Organ Sharing (UNOS), 400 adults with WD received new livers between 1987 and 2008. Most of these transplants were done in patients between the ages of 19 and 29.
Fulminant Hepatic Failure: The reason for the majority of young adult liver transplants was due to fulminant hepatic failure (FHF) also known as acute liver failure. It's the rapid deterioration of liver function. The word "hepatic" of course refers to your liver and the word "fulminant" means suddenly, like lightning. FHF also leads "encephalopathy." This is a condition in which the brain doesn't work properly because toxic substances start building up due to the liver no longer breaking them down so the body can get rid of them. In addition, there can be life-threatening brain swelling which can cause irreversible brain damage if it progresses. Therefore transplantation is considered emergent, and these patients are accorded the highest status on the waiting list for liver transplantation.
These are some of the signs and symptoms of FHF:
Ascites (uh-sigh-tees), or swelling of the abdomen when too much fluid builds up inside
Edema (uh-dee-ma), or swelling of the legs and feet
Dark, tea-colored urine and light-colored stools
Loss of appetite
Jaundice, or yellow skin and eyes
Strong feelings of irritation or confusion
FHF happens when your liver cells are injured and die. Scarring, or fibrosis, then replaces your healthy liver cells and continues until there are not enough healthy liver cells to do their job. It's important for you to know the symptoms of FHF since it can develop within a matter of days or weeks.
It is rare for FHF to be corrected with medical treatment and a transplant is life-saving for these patients..
Between the ages of 30 and 69, liver transplantation is less common in adults with WD and when it occurs the cause is fairly evenly split between FHF or a condition known as chronic liver disease (CLD) – this is, a gradual destruction of liver tissue over time. CLD can be characterized as "cirrhosis" which is when scar tissue slowly takes over normal functioning liver tissue and blocks normal blood flow through the organ. There can also be an overgrowth of scar tissue known as "fibrosis" which is a condition that can take place in almost any organ in your body.
These are some of the signs and symptoms of CLD:
Fluid buildup in the abdomen (ascites) and legs (edema)
Small red spots and tiny spider-like lines on skin
Severe nosebleeds and bleeding in the digestive tract
When a WD patient experiences FHF or advanced CLD a potentially lifesaving liver transplant may be the only treatment option.
There have been a number of scientific studies looking at how liver transplantation works in adults with WD and they are very encouraging! The largest study that followed 400 WD adults who were transplanted over a 20-year period found that almost 90% were still alive after one year; and more than 85% were still alive five years after getting their new livers. About an even number of men and women had transplants.
Studies show that in WD patients who had failing kidneys before transplantation they were able to have their kidney function restored without the need for ongoing dialysis or a second organ transplant. There's also evidence those WD patients with neurologic problems before transplant experienced improvement.
Liver transplantation cures Wilson disease and gives patients normal copper metabolism. However, anyone who receives a new liver must take medications to prevent organ rejection for life. These immune suppressing drugs can cause side effects and other long-term complications. Sadly, there is a shortage of donor organs and not nearly enough livers become available for the hundreds of people who need them each year.
Just like in adults, there are reasons why children with WD may need a liver transplant though it's less common. According to the United Network for Organ Sharing (UNOS) there were 170 liver transplants done in children with WD between 1987 and 2008. Most of them were between the ages of 10 and 18 and 70-percent were female.
The largest study done looking at why children with WD need a liver transplant shows sudden liver failure – known as "fulminant hepatic failure" (FHF) – is by far the most common cause. It's also known as acute liver failure and is the rapid deterioration of liver function. The word "hepatic" of course refers to your liver and the word "fulminant" means suddenly, like lighting. Very few children with WD needing a transplant have liver failure that develops gradually over time, which is known as "chronic liver disease" (CLD).
It may be challenging for a parent to recognize acute, or sudden liver failure in their child since the early signs can mimic other illnesses. It can look like a virus -- an upset stomach (nausea and vomiting) or feeling tired all the time (fatigue). If liver failure is the cause, then jaundice – or yellowing of the skin and eyes – will quickly develop.
Another sign for parents to look for is encephalopathy since it almost always occurs in children with liver failure, however it may be subtle in its presentation. Encephalopathy is a condition in which the brain doesn't work properly because toxic substances start building up due to the liver no longer breaking them down so the body can get rid of them. Very young children may be irritable and cry and sleep a lot. Older children may seem angry, confused, and forgetful and may have trouble falling asleep but be drowsy during the day.
Other physical signs include vomiting blood or bloody stools. Bleeding in the GI tract can be a consequence of sudden liver failure. Abdominal pain or swelling can also occur.
Again, while CLD is uncommon in children with WD these are signs that should put a parent on alert:
Itchy skin or other skin problems such as spider veins on the back, shoulders or hands
Loss of appetite and malnutrition
Easy bleeding and bruising
Pale stools or dark urine
Transplant Success Rates
As in adults, the success rates for liver transplantation in children are excellent! The largest study of children with WD who have undergone transplantation shows 90 percent were still alive five years after getting their new livers.
A genetic or family history of WD is the only known risk factor for the disease and screenings are recommended for the siblings of a child diagnosed with the disease. There are no active screening programs to identify WD in the general population, although there are discussions of newborn or early childhood screening for the disease. Scientists have found screening methods that can be used in infancy and early childhood to help identify WD. In fact, studies involving thousands of children in Asia have shown routine screenings in late infancy and preschoolers can identify children with WD long before symptoms appear. However, arguments against routine screening for any disease involve a cost-benefit analysis – a large amount of money is typically needed to identify a small number of cases.
The good news is when identified early, treatment can prevent the development of WD symptoms and usually the need for a liver transplant.
The liver is one of the few organs that can become available from either a deceased donor or a living donor. Since people with a healthy liver can safely donate a portion of it to someone whose own liver has failed, there is another potential source of donor livers. Carriers of the WD gene, parents of a child with WD or siblings of a patient, may still donate and have good liver function in the recipient.
Still, the need for donor organs is tremendous. According to the United Network for Organ Sharing (UNOS) there are more than 16,000 people on the liver transplant waiting list; about 600 of them are children. Only about 6,000 of those waiting get a new liver each year.
Regardless of where the liver comes from – a deceased or living donor – it must be a compatible match with the recipient's blood type and body weight and size.
Most liver transplants come from deceased donors – known as cadaveric transplants. Deceased donors typically die of accidents or head injuries. Either they have arranged in advance to donate their organs upon death, or family members grant permission for donation after the victim is declared brain dead.
In deceased liver donor transplants the entire organ is removed from the donor and transplanted into the recipient. Sometimes the liver is split and a portion given to both an adult and child recipient or two children. This is called a split liver donation and it's a means of expanding the donor pool so more lives can potentially be saved.
If it's determined through a transplant evaluation that you or a family member is a candidate for transplantation you are put on a national waiting list. You may wait only a few days or the wait could be months or years. UNOS maintains the waiting list and it's important to remember that because the status lists are ranked by computer and are generated as donors become available, no one at your transplant center knows your rank on the waiting list.
In 2002, the national system for allocating livers changed to one that is continually updating through the MELD/PELD severity score to prioritize those on the waiting list. UNOS developed this scoring system based on specific criteria to ensure that all people on the waiting list are judged fairly, based on how ill they are and how badly they need a transplant.
Organ allocation for adults is based on the MELD score (Model for End-Stage Liver Disease) and organ allocation for children is based on the PELD score (Pediatric End-Stage Liver Disease). The adults and children in most urgent need of a transplant are placed highest on the status list and are given first priority, and this includes patients with liver failure due to WD. Since donor organs must be transplanted within hours of being harvested from the donor, geographic location of your transplant center is also taken into account when a liver becomes available.
Waiting times are unpredictable, so the transplant team will work to keep you or your family member in the best possible health until a suitable organ becomes available.
In a living donor transplant, a segment of a healthy person's liver is transplanted into the person needing a new liver. The person who donates a portion of their liver can still live a very healthy life. Amazingly, within a few weeks of surgery the remaining segment of the donor's liver regenerates, or grows back to its full size! The same thing happens in the transplant recipient – the newly transplanted liver segment grows to the size the body needs to function normally. It's the only organ in the body that can do this!
Usually, living donor transplants occur between relatives. However, there are more and more instances of stranger-to-stranger living donor transplants, also known as altruistic donations. That is, a potential healthy donor may learn of a need and offer to go through the surgery in order to save another's life. The main advantage of a living liver donation is it can greatly reduce the recipient's waiting time. Thousands of people who need a new, healthy liver die waiting since there are not enough organs for all those on the waiting list.
Two studies evaluated living liver donations in patients with WD. They found it's safe and is an excellent treatment method for those with end-stage liver disease. These studies also showed that carriers of WD gene that are unaffected by the disease, parents and some siblings of the patient, may be donors with good recipient outcomes.
Like the transplant recipient, the living donor candidate goes through a very thorough health examination to be sure it's safe for them to donate. Since organ donation is an altruistic gift, an independent living donor advocate evaluates the potential donor to ensure donor safety, informed consent, and lack of coercion. The transplant team counsels and supports recipients, potential donors, and families through every phase of the process.
The living liver donor can expect to stay a week in the hospital following the transplant operation and needs to plan to be out of work for 2 to 3 months to fully recover. The success rates and recovery times for the recipient are about the same for both living and deceased donor transplants.
While living liver donation has become a very safe surgery with death rates below 1-percent for the donor, there are risks since it's a major operation. There can be temporary problems related to the surgical incision and the possibility of blood clots following the operation. The good news is the great majority of donors have recovered completely within a few months of their operations.
While transplantation can be a lifesaving surgery when all other treatment options are exhausted, recipients are at risk of having their body reject the new liver. Rejection occurs when the body doesn't recognize the new organ and sees it as "foreign" – the body's immune system gears up an attack against the donor liver. To prevent rejection, transplant recipients are given medicines known as "immunosuppressants." These medications have improved over the years making rejection less of a problem. However, a weaker immune system makes it harder for you to fight infections.
Rejection drugs have side effects and risks including:
Increased blood pressure
Increased risk of cancer
The actual surgery to perform removal of the diseased organ and implantation of the new, healthy liver takes 6 to 12 hours. Transplant recipients typically remain in the hospital for 3 weeks and can usually return fully to normal activities within 6 months if there are no serious complications.
If you're on a liver transplant waiting list due to chronic liver failure your doctors will advise you on how to remain as healthy as possible. Turning to transplantation means the medications used to treat WD are not an option for you. There are a number of complications that may develop with end-stage liver disease including:
Encephalopathy – that is, toxins build up in the brain causing mental changes, confusion, and possibly coma. Medications can help.
Edema or ascities – fluid builds up in the legs, feet, and abdomen. A low-salt diet and diuretics can help alleviate pressure. If needed, procedures or surgeries to reduce the pressure may be done.
Infections – antibiotics may be necessary to reduce the risk since toxins are not being cleared through the liver.
Bleeding risk – increased pressure around the portal vein and surrounding small veins may lead to bleeding in the esophagus or stomach. High blood pressure medications or endoscopic treatments may reduce this risk.
Kidney failure – sometimes when the liver stops working, so do the kidneys even if they've been previously healthy.
Kidney dialysis may be needed. The good news is that kidney function often returns to normal following a liver transplant.
Weight loss, fatigue, and jaundice are other physical symptoms of liver failure. A dietician can help you with limiting the weight loss that comes from the liver not producing the albumin needed to maintain normal muscle mass. A positive, happy atmosphere helps you continue normal activities on "up" days. Jaundice, or yellowing of the skin and eyes occurs because the liver isn't eliminating the bile that gets into the bloodstream. A side effect of jaundice is itching, which can be helped with medication. While jaundice may make you self-conscious, it shouldn't keep you from getting out of the house in order to keep spirits up.
In some cases liver failure comes on suddenly and severely, which is known as acute liver failure. The patient may have to be hospitalized until a suitable organ becomes available. Specifically for WD patients with acute liver failure, devices that lower the copper in the circulation by filtering or exchanging the blood can provide some stabilization for patients while they await transplantation. These advanced procedures are typically performed at most liver transplant centers.
If you have Wilson disease, the best way to prevent the need for a liver transplant is to take your prescribed medication! WD is a highly treatable disease with several proven therapies that can eliminate dietary copper from your body and protect your liver for life. Faithfully taking your medication means taking it every day during the intervals prescribed by your doctor. Never, ever take a break from your medication even if you're feeling well or have never experienced symptoms of WD.
Without medication WD is 100% fatal! Remember, a liver transplant is a last resort for the rare WD patients who do not respond to medical therapy or are diagnosed with the disease due to sudden liver failure. There is a shortage of livers for transplantation and while it can be a lifesaving therapy for those who do get a new liver, transplant patients must take medications for life.
Faithfully taking your medications is the best way you can take care of your liver if you have WD. However, there are other lifestyle choices you can make to help ensure you keep your liver healthy:
Eat a low-copper diet or limit your consumption of high-copper foods such as chocolate, shellfish, nuts, mushrooms, dried fruit, and liver.
Eat a healthy diet of foods from all the major food groups, get plenty of fiber, and exercise regularly to help your liver work well.
Limit or avoid alcohol since it can destroy your liver cells and those with existing liver disease can be more susceptible to damage.
Avoid breathing or touching toxins such as cleaning and aerosol products, insecticides, and other chemicals. Toxins are filtered through your liver and can damage your liver cells.
Talk to your doctor about getting vaccinated against hepatitis A and B. While hepatitis A can be spread through unsanitary conditions or contaminated food and doesn't typically linger, hepatitis B can be spread through shared body fluids and contaminated needles and lead to life-long, chronic liver disease.
See your doctor twice a year – as he or she recommends – and perform the recommended routine blood and urine testing to be sure your liver is in good health.
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“Hydroxyurea is mutagenic and clastogenic, and causes cellular transformation to a tumorigenic phenotype. Hydroxyurea is thus unequivocally genotoxic and a presumed transspecies carcinogen which implies a carcinogenic risk to humans. In patients receiving long-term hydroxyurea for myeloproliferative disorders, such as polycythemia vera and thrombocythemia, secondary leukaemia’s have been reported. It is unknown whether this leukemogenic effect is secondary to hydroxyurea or is associated with the patient's underlying disease. The physician and patient must very carefully consider the potential benefits of Trientine Hydrochloride Capsules relative to the undefined risk of developing secondary malignancies. Trientine Hydrochloride Capsules is used to treat chronic myeloid leukaemia or cervical cancer.”
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