Wilson disease or hepatolenticular degeneration is an autosomal recessive disease which results in an excess copper build up in the body. It primarily affects the liver and basal ganglia of the brain, but it can affect other organ systems too.
Symptoms usually are related to the brain and liver. Liver-related symptoms include vomiting, weakness, abdominal fluid, swelling of the legs, yellowish skin, and itchiness. Brain symptoms include tremors, muscle stiffness, trouble speaking, personality changes, anxiety, and seeing or hearing things.
Wilson disease is an autosomal recessive condition caused by a mutation in the Wilson disease protein (ATP7B) gene. For a person to be affected, they inherit a copy of the gene from each parent. Diagnosis is difficult and involves blood tests, urine tests, and a liver biopsy. Genetic testing may be used to screen the family members of those affected.
Wilson disease is caused by one of the several mutations in ATP7B gene present on chromosome 13 which controls the protein transporter responsible for excreting excess copper into bile and out of the body. The major route of copper excretion (95%) is through the liver. This excess copper first accumulates in the liver and then spills into the blood and then to other organ systems.
This disease affects 1 in every 30,000 individuals with a carrier frequency of 1 in every 90. Some populations have a higher incidence of Wilson disease due to the increased rate of consanguineous marriages. Both males and females are affected equally. The usual age of presentation is four to 40 years of age, but this disorder has been detected in children as young as three as well as adults as old as 70.
In Wilson disease, there is a faulty copper excretory mechanism, causing copper to accumulate in the liver and spill into the blood where it begins to accumulate in other organ systems like subthalamus, putamen, cortex, kidneys, and cornea. Copper is a transition metal, and excess iron levels lead to the formation of a toxic hydroxyl group and increase oxidative stress in the cells. This oxidative stress damages the cells and leads to the clinical manifestation, namely liver failure, behavioral problems, movement disorders, and Kayser-Fleisher rings in the cornea.
Copper is needed by the body, predominantly as a cofactor for some enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine beta-hydroxylase, superoxide dismutase and tyrosinase. Copper enters the body through the digestive tract with the help of a transporter protein in the cells of the small bowel, copper membrane transporter 1 (Ctr1; SLC31A1). This transporter helps to carry copper inside the cells where part of the copper is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. In response to rising copper levels, an enzyme called ATP7A releases copper into the portal vein to the liver. Liver cells carry the CMT1 protein and metallothionein, and then ATOX1 binds it inside the cell. Once here, ATP7B links the copper to ceruloplasmin and releases it into the bloodstream, removing the excess copper by secreting it into bile. Both functions of ATP7B are dysfunctional in Wilson disease. Copper accumulates in the liver, and ceruloplasmin is secreted in a form that lacks copper and is rapidly degraded in the bloodstream.
When the copper level in the liver overwhelms the proteins that normally bind it, it results in oxidative damage through a process known as Fenton chemistry. This damage results in chronic active hepatitis, fibrosis, and cirrhosis. The liver releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body, particularly in the kidneys, eyes, and brain. In the brain, copper is deposited in the basal ganglia, putamen, and globus pallidus (i.e., lenticular nucleus); these areas participate in the coordination of movement and neurocognitive processes such as stimulating mood regulation. Damage to these areas produces the neuropsychiatric symptoms seen in Wilson disease.
Since Wilson disease is a heritable disorder, patients may have a positive family history. Patients may complain of abdominal pain, jaundice, weakness, personality changes, depression, migraine headaches, insomnia, seizure, and movement disorder chorea. Hemiballismus may also be present in the history.
On physical exam, the patient may have features of hepatosplenomegaly, isolated splenomegaly, or if the disease has progressed to cirrhosis, then stigmata of chronic liver disease may also be prominent. An eye exam may reveal jaundice and Kayser-Fleischer (KF) rings (note that the only other disorder with KF rings is Primary biliary cirrhosis). Other features of Wilson disease may include the presence of movement disorders, difficulty speaking, mask-like faces, spasticity, muscle rigidity, and skin findings of lunulae ceruleae (bluish discoloration at the base of fingernails).
If suspicion of Wilson disease is high, order a ceruloplasmin level. It will be less than 20 mg/dL (normal 20 mg/dL to 40 mg/dL). Urinary copper levels will be raised more than 100 mcg/dL. These two lab findings with Kayser-Fleischer rings are usually enough for diagnosis, but if there is the possibility of an alternate diagnosis, order a liver biopsy for liver copper levels; this the most accurate test for Wilson disease. A positive result is a copper level greater than 250 mcg/g of dry liver tissue. An MRI is helpful to check for brain involvement. Liver function tests are deranged with elevated AST and ALT levels.
Wilson disease should be suspected if symptoms consistent with the disease are present or if a relative has been found to have the disease. Most had slightly abnormal liver function tests and raised aspartate transaminase, alanine transaminase, and bilirubin levels. If the liver damage is significant, albumin is decreased as a result of the inability of damaged liver cells to produce this protein; likewise, the prothrombin time is prolonged as the liver is not producing proteins known as clotting factors. Alkaline phosphatase levels are low in those with Wilson-related acute liver failure. If there are neurological symptoms, MRI of the brain should show hyperintensities in the basal ganglia in the T2 setting. MRI may demonstrate the characteristic "face of the giant panda" pattern.
There is no completely reliable test for Wilson disease, but levels of ceruloplasmin and copper in the blood, as well as copper excreted in urine during a 24-hour period, are used to form an impression of the amount of copper in the body. The gold standard is a liver biopsy.
The mainstay therapy for Wilson disease is copper chelation therapy with penicillamine and trientine. Trientine is preferred because of fewer side effects. Oral zinc also may be given as it competes for absorption with copper at metallic ion transporter.
For muscle rigidity, spasticity, and parkinsonian features, baclofen, anticholinergics, GABA antagonists, and levodopa may be used.
A diet low in copper-containing foods is recommended with avoidance of mushrooms, chocolate, nuts, dried fruit, liver, and shellfish.
Physiotherapy and occupational therapy are beneficial in the neurologic form of the disease. The copper-chelating treatment takes up to six months to start working, and these therapies can assist in coping with ataxia, dystonia, and tremors as well as preventing contractures that can result from dystonia.
Wilson disease, if untreated, will eventually lead to chronic liver disease and may even progress to hepatocellular carcinoma in some cases. Genetic counseling is necessary to prevent the transmission of the defective gene.
Wilson disease has no cure and is progressive. The disorder is best managed by a multidisciplinary team that includes a gastroenterologist, geneticist, neurologist, dietitian, nurse practitioner, pathologist, radiologist and an internist.
The mainstay therapy for Wilson disease is copper chelation therapy with penicillamine and trientine. Some patients with early disease may be offered liver transplantation. However, it is the neurological features of the disease that are difficult to manage. The patient should be educated on the consumption of low copper containing foods. Physiotherapy and occupational therapy are beneficial in the neurologic form of the disease. Genetic counseling is necessary to prevent the transmission of the defective gene.
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