Wilson’s disease, a rare autosomal recessive disorder common in populations with high rates of consanguinity, leads to abnormal copper metabolism causing hepatic and neurological dysfunction, with pathognomonic Kayser-Fleischer rings visible in the cornea and a characteristic face of the giant panda sign on brain MRI.
Description
Wilson Disease, also known as hepatolenticular degeneration, is an autosomal recessive inherited disorder of copper metabolism, leading to copper accumulation in the liver, brain, cornea, and other organs. Excessive copper can be toxic and leads to a variety of systemic symptoms.
Pathogenesis
The disease results from mutations in the ATP7B gene located on chromosome 13, which encodes a copper-transporting ATPase protein. This ATPase is primarily expressed in the liver and is involved in the incorporation of copper into ceruloplasmin and the excretion of excess copper into bile. In Wilson Disease, these processes are disrupted, leading to copper build-up within the liver. When the liver’s storage capacity is overwhelmed, copper is released into the bloodstream and deposited in various other organs, causing cellular damage and dysfunction.
Epidemiology, Risk Factors & Associations
- Wilson Disease affects approximately 1 in 30,000 individuals worldwide.
- Both genders are affected equally, and there’s no specific racial or geographical predilection.
- It usually presents in individuals aged between 6 and 20 years, although late-onset cases in older adults can occur.
- Family history is a risk factor, as the condition is inherited in an autosomal recessive manner.
Clinical Features
Clinical manifestations of Wilson Disease are highly variable and are generally related to liver disease and neurological and psychiatric disturbances.
- Liver disease can range from asymptomatic hepatomegaly and liver function test abnormalities to acute and chronic hepatitis, cirrhosis, and fulminant hepatic failure.
- Neurological features include movement disorders (tremors, dystonia, dysarthria), cognitive decline, and seizures.
- Psychiatric disturbances can range from personality changes, mood disorders, to psychosis.
- A classical feature is Kayser-Fleischer rings, a rusty-brown ring around the cornea due to copper deposition.
Complications
If left untreated, Wilson Disease can lead to severe liver disease, neurological impairment, renal disease, and can be life-threatening. Chronic active hepatitis, cirrhosis, and hepatic failure are among the significant hepatic complications.
Pathological Features
Histopathology
- In the liver, early changes include steatosis, hepatocellular apoptosis, and necrosis. Advanced disease may show cirrhosis and fibrosis.
- In the brain, there are characteristic changes in the basal ganglia with neuronal loss, gliosis, and cavitation.
Serology and Biochemistry
- Serum ceruloplasmin levels are typically low due to defective incorporation of copper into ceruloplasmin.
- Urinary copper excretion is often elevated.
- Liver function tests may reveal hepatocellular damage or cholestasis.
Genetics
Diagnosis can be confirmed with molecular genetic testing of the ATP7B gene.
Radiological Features
General Features
- Features of chronic liver disease, including cirrhosis and hepatocellular carcinoma, may be evident in advanced cases.
MRI
- T1: Deposition of copper within the basal ganglia can produce hyperintensities.
- T2: Similarly, T2-weighted images may show hyperintensities in the basal ganglia, particularly in the putamen. In later stages, T2 hyperintensities may appear in the midbrain, thalamus, and white matter.
Differential Diagnosis
The differential diagnosis for Wilson Disease is broad due to its wide-ranging clinical manifestations. These include other causes of liver disease (such as autoimmune hepatitis, viral hepatitis), movement disorders (like Parkinson’s disease), and psychiatric conditions.
Management
- Neurologists and hepatologists typically manage Wilson Disease.
- Treatment aims to reduce copper accumulation using chelating agents like penicillamine or trientine, or zinc therapy to reduce intestinal copper absorption.
- In severe or refractory cases, liver transplantation can be considered.
- Genetic counselling should be offered to affected individuals and their families.