Wilson's disease

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Wilson’s disease is a rare autosomal recessive inherited disease that occurs in both children and adults due to copper accumulation in different organs, mainly in the liver and the brain. Wilson’s disease is caused by genetic mutations in the ATP7B gene which is responsible for the transportation of the dietary copper to the liver. Copper is normaly absorbed in the stomach and transported to the liver in order to function properly as a cofactor for some enzymes as the cytochrome c oxidase enzyme. Copper is also incorporated in the formation of ceruloplasmin in the Trans Golgi network. Transportation of the copper to the Trans Golgi network occurs via ATOX1 protein and others are bound to metallothionein. Pathogenesis of Wilson’s disease include any impairment that may occur during copper transportation and incorporation into different essential metabolic mechanisms. The mechanisms responsible for the pathogenesis of Wilson’s disease include high serum copper level, accumulation of the copper in the liver, and deposition of the copper in different organs resulting in ultimate injury and organ damage. The prevalence of Wilson’s disease is estimated to be 3 cases per 100,000 individuals worldwide. Wilson’s disease affects individuals between 5 to 35 years old. Common risk factors of Wilson’s disease include newborns of disease-carrier parents. Less common risk factors include excess non-vegetarian diet. If left untreated, Wilson’s disease will lead to death as the copper accumulation in the liver and brain results in cirrhosis and severe dystonia, respectively. Common complications of Wilson’s disease include hepatocellular carcinoma, renal failure, and persistent neurological manifestations. Prognosis of Wilson’s disease is usually good in case of early detection and proper treatment. Patients with Wilson’s disease may remain asymptomatic until the copper deposits in the liver and brain mainly. Common hepatic symptoms include abdominal distension, abdominal pain, fatigue, bleeding tendency, and esophageal varices. Common neuropsychiatric symptoms include tremors, ataxia, dysarthria, and impulsiveness. Physical examination of patients with Wilson’s disease is usually remarkable for jaundice and easy bruising in the skin. Physical examination also is remarkable for Kayser-Fleischer ring in the eyes as a result of the copper accumulation in the cornea. Laboratory findings suggestive for Wilson’s disease include low ceruloplasmin level, high serum copper concentration and high urinary excretion of the copper. MRI scanning can be used in detecting brain abnormalities especially in the basal ganglia. Medical therapy is the mainstay of therapy for treatment patients with Wilson’s disease. The treatment option include penicillamine, trientine, and Zinc. Liver transplantation is reserved for the patients that present with acute liver failure and unresponsive to the medical treatment.

Wilson’s disease was first described by Dr. Samuel Alexander Kinnier Wilson at which he described the pathological changes in the brain and liver in 1912. Many research studies revealed the correlation between ATP7B gene mutation and Wilson’s disease. The first effective oral chelator was discovered by Dr. Walshe in 1956.

Wilson’s disease is classified based on the symptomatic presentation into hepatic and neurologic Wilson’s disease.

Copper is one of the essential elements for the human body. Copper must be absorbed and transported in order to function properly. Copper is transported bound to metallothionein or carried by ATOX1 to the trans-Golgi network. Impairment of copper incorportation in formation of ceruloplasmin will lead to increase the serum level of the copper. The increase of copper level will lead to accumulation of the excess amount in the liver and other organs. ATP7B gene mutation is found in the majority of the patients with Wilson’s disease. 

Wilson’s disease is caused by ATP7B gene mutation and impairement of copper transportation. 

Wilson’s disease must be differentiated from other diseases that cause jaundice like hemochromatosis, viral hepatitis, alcoholic hepatitis, drug induced hepatitis, and autoimmune hepatitis.

The prevalence of Wilson’s disease is estimated to be 3 cases per 100,000 individuals worldwide. Wilson’s disease affects individuals between 5 to 35 years old.

Commpn risk factors of Wilson’s disease include newborns of disease-carrier parents. Less common risk factors inlcude excess non-vegetarian diet.

There is insufficient evidence to recommend routine screening for Wilson’s disease.

If left untreated, Wilson’s disease will lead to death as the copper accumulation in the liver and brain results in cirrhosis and severe dystonia respectively. Common complications of Wilson’s disease include hepatocellular carcinoma, renal failure, and persistent neurological manifestations. Prognosis of Wilson’s disease is usually good in case of early detection and proper treatment.

Wilson’s disease diagnostic criteria is based on scoring system which includes clinical presentation, laboratory findings, and gene mutation analysis. The score of 4 or more is diagnostic for Wilson’s disease. The score of 2 or less is ruling out Wilson’s disease.

Patients with Wilson’s disease may remain asymptomatic until the copper deposits in the liver and brain mainly. Common hepatic symptoms include abdominal distension, abdominal pain, fatigue, bleeding tendency, and esophageal varices. Common neuropsychiatric symptoms include tremors, ataxia, dysarthria, and impulsiveness. Less common symptoms of wilson’s disease include urolithiasis and hematuria. 

Patients with Wilson’s disease usually appear tired. Physical examination of patients with Wilson’s disease is usually remarkable for jaundice and easy bruising in the skin. Physical examination also is remarkable for Kayser-Fleischer ring in the eyes as a result of the copper accumulation in the cornea. Common physical examination findings in the abdomen include abdominal tenderness, ascites, and spider angiomata. Common neuropsychiatric signs include seizures, parkinsonism like signs, depression, and anxiety.

Laboratory findings suggestive for Wilson’s disease include low ceruloplasmin level, high serum copper concentration, and high urinary excretion of thecopper.

There are no EKG findings associated with Wilson’s disease. However, if the heart is affected by Wilson’s disease, EKG should be performed to exclude any concurrentarrhythmias.

There are no x-ray findings associated with Wilson’s disease.

There are no ultrasound findings associated with Wilson’s disease.

CT scan can be used in detecting abnormalities in the brain but MRI is more sensetive in diagnosing Wilson’s disease associated with neurological manifestations.

There are no specific MRI findings associated with Wilson’s disease especially in cases who present with only hepatic manifestations. However, it may show abnormalities in the basal ganglia in the patients who presented with neuropsychiatric manifestations.

There are no other imaging findings associated with Wilson’s disease.

Liver biopsy is performed in suspected cases of Wilson’s disease as it may show many histopathological features. Liver biopsy may show mild steatosis, hepatocellular necrosis, macronodular cirrhosis, and fulminant liver failure features as parenchymal collapse. Genetic testing is also recommended in Wilson’s disease to obtain the family history of the disease and for early detection.

Medical therapy is the mainstay of therapy for treatment patients with Wilson’s disease. The treatment option include copper chelators as penicillamine and trientine. The treatment also includes Zinc to prevent copper reaccumulation.

Surgery is not the first-line treatment option for patients with Wilson’s disease. Surgery is usually reserved for patients with acute hepatitis and unresponsive to the medical therapy. Liver transplantation is recommended in patients with acute liver failure.

Effective measures for the primary prevention of Wilson’s disease include genetic analysis of the family members in order to early detect and treat the disease.

The primary and secondary prevention strategies for Wilson’s disease are the same.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Copper is one of the essential elements for the human body. Copper must be absorbed and transported in order to function properly. Copper is transported bound to metallothionein or carried by ATOX1 to the trans-Golgi network. Impairment of copper incorportation in formation of ceruloplasmin will lead to increase the serum level of the copper. The increase of copper level will lead to accumulation of the excess amount in the liver and other organs. ATP7B gene mutation is found in the majority of the patients with Wilson’s disease.

• Copper is one of the essential elements that is required daily in diet in a range of 1.5 to 2 mg.^[1]
• Copper is incorporated in number of important functions in the body. It functions as a component of some enzymes as cytochrome c oxidase, dopamine β-hydroxylase, superoxide dismutase and tyrosinase.^[2]
• In order to function appropriately, a significant proportion of copper must be absorbed and transported to the different site of actions. Stomach and duodenum are the main sites of absorption of copper then it binds albumin and transported to different body tissues. The excess copper is excreted as feces after being a part of the bile.
• Copper is carried inside the cells by a transporter protein on the cells of the small bowel called copper membrane transporter 1 (CMT1). Others are bound to metallothionein where the rest is carried by ATOX1 to the trans-Golgi network.
• Transportation of the copper to different body tissues is regulated by ATP7B gene in the hepatocytes.
• ATP7B gene acts on transporting copper via two ways:^[3][4]
  • In the trans-golgi network: Formation of ceruloplasmin (which is secreted into the blood) by adding the copper to the apoceruloplasmin.
  • In the cytoplasmic vesicles: Excretion of the excess copper into the bile by exocytosis against the hepatocytes memebrane.

• The following table includes the main mechanisms that play an important role in pathogenesis of Wilson’s disease.

• ATP7B gene mutation is the main cause of copper transportation impairment and Wilson’s disease.
• ATP7B gene placed on chromosome 13 and is expressed primarily in the liver, kidney, and placenta.
• Wilson’s disease ATP7B gene mutation is inhereted in an autosomal recessive pattern. The majority of the patients have no family history.

• Wilson’s disease may be associated with the following conditions:^[5]
  • Fulminant liver failure
  • Cirrhosis
  • Aceruloplasminaemia

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

• Histological examination of a liver biopsy may show the following:^[6]
  • Mild steatosis which is considered an early histological feature
  • Glycogenated hepatic nuclei
  • Hepatocellular necrosis
  • Autoimmune hepatitis histologic features
  • Fibrosis and cirrhosis (macronodular or micronodular) in advanced cases
  • Fulminant liver falilure features which include:
    • Hepatocellular degenration
    • Parenchymal collapse

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