Wilson Disease

-Wilson's disease is named after Samuel Alexander Kinnier Wilson (1878–1937), the British neurologist who first described the condition in 1912.-Wilson disease is inherited autosomal recessive disease.-A single abnormal copy of the gene is present in 1 in 100 people.-The incidence is 1-4/100000-The abnormal gene for welsion disease is located on the long arm of chromosome -13-. -Because of the abnormal gene there is defect in the biliary copper excretion , and copper incorporation into ceruloplasmin.-Wilson disease is a multisystem disorder it involves liver,brain,eye,blood,kidney, and endocrine glandes.

Pathogenesis

-Absence or malfunction of the gene results in decreased biliary copper excretion and diffuse accumulation of copper in the cytosol of hepatocyte.-When liver cells become overloaded, copper is redistributed to other tissues including the brain and kidneys, to which it is toxic,primarly as a potent inhibitor of enzymatic processes.

Pathology

-There is degenerative changes in the brain, liver and kayser-Fleischer rings in the cornea.-All grades of hepatic injury occure,there is progressive parenchymal damage,fibrosis,and cirrhosis.-Ultrastractural changes primarily involves mitochondria.

CLINICAL MANIFESTATION

Wilson disease can be presents with any form of liver disease after the age of -5-years,but mutation that completely knock out gene function are associated with disease onset as early as ( 2-3)years of age.

Wilsonian hepatic disease include:-Asymptomatic hepatomegaly with or without splenomegaly.-Sub acute or chronic hepatitis.-Fulminant hepatic failure, three times more common in female-Liver cirrhosis with portal hypertention,ascites edema,varecial bleeding.-Other effects of hepatic dysfunction like: delayed puberty,amenorrhea,coagulation defect.

CLINICAL MANIFESTATION

Neurological manifestations:After-20-years of age, neurologic symptoms predominate.Neurologic disorders may present with:-Intention tremor.-Dysarthria.-Dystonia.-Lack of motor coordination.-Deterioration in school performance.-Behavior changes.-Kayser-Fleischer ring always present in patient with neurological manifestation.- Wilson's disease is also associated with sunflower cataracts exhibited by brown or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual loss.

Psychiatric manifestation:-Depression.-Anxiety.-Psychosis.

Hematological manifestation:Wilson disease may present for the first time with coombs test negative hemolytic anemia, possibly related to the release of large amount of copper from damaged hepatocytes.

Renal manifestation:Wilson disease may present with renal fanconi syndrome which include:-Aminoaciduria.-Glycosuria.-phosphaturia.-Renal tubular acidosis.-Progressive renal failure.

*Unusual manifestation include: arthritis,cardiomyopathy,endocrinopathy.

DIAGNOSIS

Wilson disease should be in the differential diagnosis of children or teenager presenting with:1-Unexplained acute or chronic liver disease.2-Neurologic symptoms of unknown cause.3-Acute hemolysis.4-Psychiatric illness.5-Behaiveral changes.6-Fanconi syndrome.

LABORATORY INVESTIGATIONS

1-Cerulopasmin:the best screening test is to measure the serum ceruloplasmin level, most patients have decreased cerulopasmin level,caution must be used in interpreting ceruloplasmin level as they may be elevated in acute inflammation and in states of elevated estrogen such as pregnancy, estrogen supplimentation,or oral contraceptive use.2-Serum copper: The serum copper level may be elevated in early wilson disease.

3-Urinary copper: urinary copper excretion is normally <40ug/day,in patient with Wilson disease is increased to >100ug/day,and often up to 1000 ug /day or more.In equivocal cases urinary copper output in response to chelation may be of diagnostic help.

4-Liver biopsy:Liver biopsy is for diagnosis, and for determining the extent and severity of liver disease, normal copper content of liver is( <10ug/gm dry weight).In Wilson disease hepatic copper content exceeds 250ug/gm dry weight.

5-Genetic screening:There are more than 250 mutations in the gene have been identified, making diagnosis by DNA mutational analysis a difficult task unless a proband mutation is known.--Family members of patient with proven cases of Wilson should be screened by:-Kayser-Flescher ring.-Serum ceruloplasmin level.-Urinary copper excretion. If these result are abnormal or equivocal, liver biopsy should be carried out.

TREATMENT

Wilson disease is progressive and fatal ,but effective treatment is available.1-Copper intake:Copper intake should be restricted to <1mg/day.Foods such as liver,shellfish,nuts,and chocolate should be avoided.If copper content of drinking water exceed 0.1mg/L ,it may be necessary to demineralize.

2-copper chelating agent:Administration of copper chelating agent leads to rapid excretion of excess deposited copper.Best chelating agent is oral D-penicillamine in dose of 20mg/kg/day.Patient with neurological manifestation 10-50% of them when initially receive D-penicillamin have a worsening thir symptomes.

Side effects of D-penicillamin include:1-Goodpature syndrome.2-Systemic lupus erythematosis.3-Polymyositis.4-Aplastic anemia.5-Nephrosis.6-Deficiency of other elements like zinc.7-Vitamin B6 deficiency.

For those patient who can not tolerate D-penicillamin,other chelating agent can be use like:1-Triethylene tetramine dihydrochloride in dose of 20mg/kglday.2-Ammonium tetrathiomolybdate is a new agent under investigation for patient with neurological manifestation.side effectes include:anemiam,lucopenia,thrombocytopenia.

3-Zinc therapy:Zinc has been used as adjuvant therapy,maintenance therapy,or primary therapy.Mecanism of action:it impair the gastrointestinal absorbtion of copper.Dose : 25mg/8hr in children above the age of five years.

4-Liver transplantation: is indicated for patient with fulminant liver failure,decompensated cirrhosis,Liver transplantation is curative with survival rate of 85-90%.

PROGNOSIS

Untreated patient with Wilson disease die of hepatic,neurologic,renal or hematologic complication.The prognosis for patients receiving penicilammin variable depends on time of initiation and the individual response to chelation.In asymptomatic patient ,early initiation of chelation therapy prevent expression of the disease.