Wilson`s Disease

What is Wilson`s Disease?

Wilson`s disease is a genetic disorder in which excess copper builds up in the body. It 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 caused by mutation of the ATP7B gene, which results in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin. This disorder is marked by the accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye.

Normally 40% to 60% of ingested copper (2 5 mg/day) is absorbed in the duodenum and proximal small intestine, from where it is transported complexed with albumin and histidine to the liver.

Free copper dissociates and is taken up by hepatocytes, where copper is incorporated into enzymes and 2-globulin (apoceruloplasmin) to form ceruloplasmin, which is secreted into the blood. Ceruloplasmin carries 90% to 95% of plasma copper. Circulating ceruloplasmin is eventually desialylated, endocytosed by the liver, and degraded within lysosomes, after which the released copper is excreted into bile. This degradation/excretion pathway is the primary route for copper elimination.

The ATP7B gene, located on chromosome 13, encodes a transmembrane copper-transporting ATPase that is expressed on the hepatocyte canalicular membrane. The overwhelming majority of patients with Wilson disease are compound heterozygotes with different loss-of-function mutations affecting each ATP7B allele. Loss of ATP7B protein function impairs the transport of copper into the bile and the incorporation of copper into ceruloplasmin, which is not secreted in its apoceruloplasmin form. These abnormalities lead to copper accumulation in the liver and a decrease in plasma ceruloplasmin.

Most patients with Wilson s disease present with one or more of:

Hepatic problems (40%) , Neurological Problems (50%), Psyciatric problems (10%)

Copper deposition in the liver leads to Chronic Hepatitis and eventually liver cirrhosis, in CNS can lead to neurological problems like Dysarthria (speech difficulties) and dystonia (abnormal muscle tone) and if copper is deposited in basal ganglia it can result in Parkinsonism like symptoms, and psychiatric problems which varies from mild depression to full psychosis.

Kayser Fleischer rings in cornea (deposition of copper in Descemet s corneal membrane) which are brownish circles surrounding the iris and can be seen by the naked eye, proper assessment is made using slit lamp examination.

Other features include: Haemolytic anemia , Renal tubular damage leading to renal tubular acidosis and osteopenia (loss of bone density)

Asymptomatic cases usually involve only minimal fatty degeneration. Mallory bodies are present in some cases. Copper is usually deposited in the periportal hepatocytes in the form of reddish granules in the cytoplasm or as reddish cytoplasmic coloration, stainable by rubeanic acid or rhodamine stains for copper. . Symptomatic cases involve a feather-like pattern of vacuolar liver cell degeneration leading to chronic liver inflammation with progressive parenchymal destruction (chronic aggressive hepatitis). This later progresses to liver cirrhosis

Involvement of basal ganglia in the brain is seen in the form of toxic injury to neurons. In the cornea as greenish-brown deposits of copper in Descemet s membrane. In the kidney as fatty and hydropic change

Management:-

• The mainstay of therapy for Wilson disease is pharmacologic treatment with chelating agents such as D-penicillamine and trientine. Other agents include sodium dimercaptosuccinate, dimercaptosuccinic acid, zinc, and tetrathiomolybdate. Zinc salts act as inductors of methallothioneins, which favor a negative copper balance and a reduction of free plasmatic copper.
• With clinical progression, acute liver failure, or worsening hepatic function, the patient must be evaluated for liver transplantation.
• Diet: Patients should generally avoid eating foods with a high copper content
• Lifelong, uninterrupted chelation therapy is necessary in all patients with Wilson disease.