ABOUT AUTHOR:
Akshay Rajgaria
Kanak Manjari Institute of pharmaceutical Sciences.
Rourkela, Orissa
akshaykrish2007@gmail.com
ABSTRACT:
Wilson disease (WD) is an autosomal recessive disorder characterized by toxic accumulation of copper in the liver and subsequently in the brain and other organs. On the basis of sequence homology to known genes, the WD gene (ATP7B) appears to be a copper-transporting P-type ATPase.
REFERENCE ID: PHARMATUTOR-ART-2062
INTRODUCTION:
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.
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. It is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912.
CAUSES:
In Wilson's disease, a particular gene on chromosome 13 does not work. The gene is called ATP7B. This gene normally controls the way the liver cells get rid of excess copper. Normally, the liver cells pass out excess copper into the bile. If this process does not work then the copper builds up in liver cells. When the copper storage capacity of the liver cells is exhausted, the copper spills into the bloodstream and deposits in other parts of the body, mainly the brain.
SIGN AND SYMPTOM:
Sign and symptoms of Wilson's disease include:
- Clumsiness
- Depression
- Difficulty speaking
- Difficulty swallowing
- Difficulty walking
- Drooling
- Easy bruising
- Fatigue
- Involuntary shaking
- Joint pain
- Loss of appetite
- Nausea
- Skin rash
- Swelling of arms and legs
- Yellowing of the skin and eyes (jaundice).
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 (CMT1), 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 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 it is ATP7B that 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 apoceruloplasmin) 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 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 as well as playing 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.
It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that high levels of free (non-ceruloplasmin bound) copper have a direct effect on either oxidation of hemoglobin, inhibition of energy-supplying enzymes in the red blood cell, or direct damage to the cell membrane.
TREATMENT: Medical 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 observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. Those 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. A further agent with known activity in Wilson's disease is tetrathiomolybdate. This is regarded as experimental, though some studies have shown a beneficial effect.
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.
In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol (British anti-lewisite) is occasionally necessary. This treatment is injected intramuscularly (into a muscle) every few weeks and has unpleasant side effects such as pain.
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.
REFERENCES:
• Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007). "Wilson's disease". Lancet 369 (9559): 397–408
• Kinnier Wilson SA (1912). "Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver"
• De Bie P, Muller P, Wijmenga C, Klomp LW (November 2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes"
• Lee, GR (1999). "Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents". In Lee GR, Foerster J, Lukens J et al... Win robe’s clinical hematology. Vol 1 (10th Ed.). Williams & Wilkins. p. 1298.
• Roberts EA, Schilsky ML (2003). "A practice guideline on Wilson disease" (PDF). Hepatology 37 (6): 1475–92.
• Walshe JM (July 1996). "Treatment of Wilson's disease: the historical background". QJM 89 (7): 553–5.
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