Wilson's disease (also called hepatolenticular degeneration) is a genetic disorder characterized by the excess build-up of copper 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 in speaking, personality changes, anxiety, and psychosis.
Wilson's disease occurs in about one in 30,000 people. Symptoms usually begin between the ages of 5 and 35 years. It was first described in 1854 by German pathologist Friedrich Theodor von Frerichs and is named after British neurologist Samuel Wilson.
Wilson's disease is caused by a mutation in the Wilson disease protein (ATP7B) gene. This protein transports excess copper into bile, where it is excreted in waste products. The condition is autosomal recessive; for people to be affected, they must inherit a mutated copy of the gene from both parents. 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 and kidney problems. A liver transplant may be helpful to those for whom other treatments are not effective or if liver failure occurs.
Signs and symptoms The main sites of copper accumulation are the liver and brain. Consequently, liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. People with liver problems tend to come for medical attention earlier (generally as children or teenagers) than those with neurological and psychiatric symptoms, who tend to be in their 20s or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but have not received a diagnosis.
Liver disease Liver disease may present itself as tiredness, jaundice, increased bleeding tendency or confusion (due to hepatic encephalopathy), and portal hypertension. The last, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices as well as splenomegaly and ascites. On examination, signs of chronic liver disease such as spider angiomata (small, distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has already caused cirrhosis of the liver in most patients by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively low in Wilson's disease.
About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of hemolytic anemia (anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products, such as ammonia, in the bloodstream. When these irritate the brain, patients develop hepatic encephalopathy – a serious condition that causes confusion, coma, seizures and, finally, life-threatening swelling of the brain).
Neuropsychiatric symptoms
About half of people with Wilson's disease have neurological or psychiatric symptoms. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms usually then follow, often in the form of parkinsonism (lead-pipe or cogwheel rigidity, bradykinesia, and postural instability) with or without a typical hand tremor, masked facial expressions, slurred speech, ataxia (lack of coordination), or dystonia (twisting and repetitive movements of part of the body). Seizures and migraine appear to be more common in Wilson's disease. A characteristic tremor described as "wing-beating tremor" is encountered in many people with Wilson's; this is absent at rest but can be provoked by abducting the arms and flexing the elbows toward the midline.
Cognition can also be affected in Wilson's disease, in two non-mutually exclusive categories: frontal lobe disorder (may present as impulsivity, impaired judgement, promiscuity, apathy, and executive dysfunction with poor planning and decision-making) and subcortical dementia (may present as slow thinking, memory loss, and executive dysfunction, without signs of aphasia, apraxia, or agnosia). These cognitive involvements are thought to be related and closely linked to psychiatric manifestations of the disease.
Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety disorders, and psychosis. Psychiatric symptoms are commonly seen in conjunction with neurological symptoms and are rarely manifested on their own. These symptoms are often poorly defined and can sometimes be attributed to other causes. Because of this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present.
Other organ systems
Medical conditions have been linked with copper accumulation in Wilson's disease: Eyes: Kayser–Fleischer rings (KF rings) may be visible in the cornea of the eyes, either directly or on slit lamp examination, as deposits of copper form a ring around the cornea. This is due to copper deposition in Descemet's membrane of the cornea. These rings can be either dark brown, golden, or reddish green, are 1 to 3mm wide, and appear at the corneal limbus. They do not occur in all people with Wilson's disease and may also be seen in people with chronic cholestasis. Wilson's disease is also associated with sunflower cataracts exhibited by brown or green pigmentation of the anterior and posterior lens capsule. Neither causes significant visual loss. KF rings occur in approximately 66% of diagnosed cases (more often in those with neurological symptoms rather than with liver problems). Kidneys: renal tubular acidosis (Type 2), a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis (calcium accumulation in the kidneys), a weakening of bones (due to calcium and phosphate loss), and occasionally aminoaciduria (loss of essential amino acids needed for protein synthesis). Heart: cardiomyopathy (weakness of the heart muscle) is a rare but recognized problem in Wilson's disease; it may lead to heart failure (fluid accumulation due to decreased pump function) and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat). Hormones: hypoparathyroidism (failure of the parathyroid glands leading to low calcium levels), panhypopituitarism (leading to decreased production of hormones from the pituitary gland), infertility, and recurrent miscarriage. Musculoskeletal: Arthritis and thinning of the bones (osteopenia or osteoporosis). Fingers: Blue nails, or more formally Azure Lunula, is seen as a blue colouring fading proximally.
Genetics
The Wilson's disease gene (ATP7B) is on chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney, and placenta. The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin. Most people who have Wilson's disease – 60% – are homozygous for ATP7B mutations (two abnormal copies), and 30% of them have only one abnormal copy. In up to 7% of cases, people with Wilson's disease have no detectable mutations.
Although more than 500 mutations of ATP7B have been described, a very small number of those cause most cases of Wilson's disease; which mutation an individual will have tends to be specific to the population they are part of. For instance, in Western populations, the H1069Q mutation (replacement of a histidine by a glutamine at position 1069 in the protein) is present in 37%–63% of cases, while in China this mutation is very uncommon; R778L (arginine to leucine at 778) is found more often there. Relatively little is known about the relative impact of the various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies. A comprehensive clinically annotated resource, WilsonGen, provides a clinical classification for the variants as per the recent ACMG & AMP guidelines.
A normal variation in the PRNP gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE gene was initially suspected, but could not be confirmed.
The condition is inherited in an autosomal recessive pattern. To inherit it, both of the parents of an individual must carry an affected gene. Most people with Wilson's disease have no family history of the condition. People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.
There are several hereditary diseases that cause copper overload in the liver; Wilson's disease is the most common of them. All can cause cirrhosis at a young age. The other copper overload diseases are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis, and idiopathic copper toxicosis. These three, unlike Wilson's disease, are not related to ATP7B mutations; for example, ICC has been linked to mutations in the KRT8 and the KRT18 genes.
Pathophysiology
Copper is needed by the body for a number of functions, predominantly as a cofactor for a number of enzymes such as ceruloplasmin, cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase, and tyrosinase.
Copper enters the body through the digestive tract. A transporter protein on the cells of the small bowel, copper membrane transporter 1 (Ctr1; SLC31A1), carries copper inside the cells, where some is bound to metallothionein and part is carried by ATOX1 to an organelle known as the trans-Golgi network. Here, in response to rising concentrations of copper, an enzyme called ATP7A (Menkes' protein) releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here, ATP7B links copper to ceruloplasmin and releases it into the bloodstream, as well as removing excess copper by secreting it into bile. Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apo-ceruloplasmin) and is rapidly degraded in the bloodstream.
When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage to the liver through a process known as Fenton chemistry; this damage eventually leads to chronic active hepatitis, fibrosis (deposition of connective tissue), and cirrhosis. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body, but particularly in the kidneys, eyes, and brain. In the brain, most copper is deposited in the basal ganglia, particularly in the putamen and globus pallidus (together called the lenticular nucleus); these areas normally participate in the coordination of movement and play a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease.