Wilson's disease overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]
Overview
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.
Historical Perspective
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.
Classification
Wilson's disease is classified based on the symptomatic presentation into hepatic and neurologic Wilson's disease.
Pathophysiology
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.
Causes
Wilson's disease is caused by ATP7B gene mutation and impairement of copper transportation.
Differentiating Wilson's disease from Other Diseases
Wilson's disease must be differentiated from other diseases that cause jaundice like hemochromatosis, viral hepatitis, alcoholic hepatitis, drug induced hepatitis, and autoimmune hepatitis.
Epidemiology and Demographics
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.
Risk Factors
Commpn risk factors of Wilson's disease include newborns of disease-carrier parents. Less common risk factors inlcude excess non-vegetarian diet.
Screening
There is insufficient evidence to recommend routine screening for Wilson's disease.
Natural History, Complications, and Prognosis
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.
Diagnosis
Diagnostic study of choice
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.
History and Symptoms
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.
Physical Examination
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
Laboratory findings suggestive for Wilson's disease include low ceruloplasmin level, high serum copper concentration, and high urinary excretion of thecopper.
Electrocardiogram
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.
X-ray
There are no x-ray findings associated with Wilson's disease.
Ultrasound
There are no ultrasound findings associated with Wilson's disease.
CT scan
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.
MRI
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.
Other Imaging Findings
There are no other imaging findings associated with Wilson's disease.
Other Diagnostic Studies
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.
Treatment
Medical Therapy
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
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.
Primary prevention
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.
Secondary prevention
The primary and secondary prevention strategies for Wilson's disease are the same.