Wilson's disease

موضوع: Wilson's disease الأحد سبتمبر 18, 2011 1:50 pm

Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder in which copper accumulates in tissues; this manifests as neurological or psychiatric symptoms and liver disease. It is treated with medication that reduces copper absorption or removes the excess copper from the body, but occasionally a liver transplant is required.[1]

The condition is due to mutations in the Wilson disease protein (ATP7B) gene. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carriers). If a child inherits the gene from both parents, the child may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson's disease occurs in 1 to 4 per 100,000 people.[1] Wilson's disease is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912

Signs and symptoms

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.[1] People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties 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 haven't received a diagnosis.[3]

Liver disease

Liver disease may present as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) and portal hypertension. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices, blood vessels in the esophagus that may bleed in a life-threatening fashion, as well as enlargement of the spleen and accumulation of fluid in the abdominal cavity. On examination, signs of chronic liver disease such as spider naevi (small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma (liver cancer), this risk is relatively very low in Wilson's disease.[1]

About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a 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, the person develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain)

Neuropsychiatric symptoms

About half the people with Wilson's have neurological or psychiatric problems. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms then follow, often in the form of parkinsonism (cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonism features[4]) 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.[1] Cognition can also be affected in Wilson's disease. This comes in two, not 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). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.[4]

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety and psychosis.[1] Psychiatric symptoms are commonly seen with the neurological symptoms, they rarely manifest on their own. These symptoms are often not well defined and can be attributed to other causes. Due to this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present

Other organ systems

Various medical conditions have been linked with copper accumulation in Wilson's disease:
Eyes: Kayser–Fleischer rings (KF rings) may be visible around the iris. They are due to copper deposition in Descemet's membrane of the cornea. They do not occur in all people and may only be visible on slit lamp examination. Wilson's disease is also associated with sunflower cataracts, brown or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual loss.[1] KF rings occur in 66% of cases, more often in those with neurological than with liver problems.[3]
Kidneys: renal tubular acidosis, a disorder of bicarbonate handling by the proximal tubules leads to nephrocalcinosis (calcium accumulation in the kidneys), weakening of the bone (due to calcium and phosphate loss) and occasionally aminoaciduria (loss of amino acids, needed for protein synthesis).[1]
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).[1]
Hormones: hypoparathyroidism (failure of the parathyroid glands, leading to low calcium levels), infertility and habitual abortion

Diagnosis

Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's. Most have slightly abnormal liver function tests such as a raised aspartate transaminase, alanine transaminase and bilirubin level. If the liver damage is significant, albumin may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time (a test of coagulation) may be prolonged as the liver is unable to produce proteins known as clotting factors.[1] Alkaline phosphatase levels are relatively low in those with Wilson's-related acute liver failure.[9] If there are neurological symptoms, magnetic resonance imaging (MRI) of the brain is usually performed; this shows hyperintensities in the part of the brain called the basal ganglia in the T2 setting.[7] MRI may also demonstrate the characteristic "face of the giant panda" pattern.[10]

There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard or most ideal test is a liver biopsy

Treatment

Dietary

In general, a diet low in copper-containing foods is recommended, with the avoidance of mushrooms, nuts, chocolate, dried fruit, liver, and shellfish.[1]

Medication

Various treatments are available for Wilson's disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.

Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus (causing joint pains and a skin rash) or myasthenia (a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment.[1][7] Intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive.[7] A further agent with known activity in Wilson's disease is tetrathiomolybdate. This is still regarded as experimental,[7] although some studies have shown a beneficial effect.[1]

Once all results have returned to normal, zinc (usually in the form of a zinc acetate prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases.[7]

In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-Lewisite) is still occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.[11]

People who are asymptomatic (for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.[7]

Physical therapy

Physiotherapy is beneficial for those patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and physical therapy can assist in coping with ataxia, dystonia, and tremors, as well as preventing the development of contractures that can result from dystonia.[12]

Transplantation

Liver transplantation is an effective cure for Wilson's disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment, or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.

موضوع: رد: Wilson's disease الأحد سبتمبر 18, 2011 2:58 pm

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