From the Guidelines
Wilson disease is a genetic disorder characterized by excessive copper accumulation in the body, particularly in the liver, brain, and eyes, due to mutations in the ATP7B gene, which encodes a copper-transporting protein primarily expressed in the liver. The pathophysiology of Wilson disease centers on the defective function of the ATP7B protein, which normally helps incorporate copper into ceruloplasmin (a copper-carrying protein in blood) and facilitates copper excretion into bile 1. When ATP7B is defective, copper cannot be properly excreted from the liver into bile or incorporated into ceruloplasmin, leading to copper accumulation in hepatocytes. As liver copper levels rise, the metal eventually spills into the bloodstream as free copper, which deposits in other tissues including the brain, kidneys, and cornea.
Key Features of Wilson Disease
- Liver disease and cirrhosis
- Neuropsychiatric disturbances
- Kayser-Fleischer rings in Descemet's membrane of the cornea
- Acute episodes of hemolysis often in association with acute liver failure
In the liver, copper accumulation causes oxidative damage, inflammation, and eventually hepatocyte death, leading to chronic hepatitis, cirrhosis, and liver failure. In the brain, copper deposition damages the basal ganglia and other structures, resulting in neurological symptoms like tremors, dystonia, and psychiatric disturbances. The characteristic Kayser-Fleischer rings in the eyes result from copper deposition in Descemet's membrane of the cornea. Wilson disease follows an autosomal recessive inheritance pattern, requiring two defective copies of the ATP7B gene for disease manifestation, though the severity and age of onset can vary considerably among affected individuals 1.
Diagnosis and Treatment
The diagnosis of Wilson disease is based on a combination of clinical, biochemical, and genetic findings, including low serum ceruloplasmin levels, high urinary copper excretion, and mutation analysis of the ATP7B gene 1. Treatment options include chelating agents, such as penicillamine and trientine, and zinc therapy, which can help reduce copper accumulation and prevent further damage to the liver and brain 1.
Importance of Early Diagnosis and Treatment
Early diagnosis and treatment of Wilson disease are crucial to prevent long-term damage to the liver and brain, and to improve quality of life and survival rates 1. A low serum ceruloplasmin level should be taken as evidence for the diagnosis of Wilson’s disease, and basal 24-hour urinary excretion of copper >1.6 μmol is typical in symptomatic patients 1. Hepatic parenchymal copper content >4 μmol/g dry weight provides critical diagnostic information and should be obtained in cases where the diagnosis is not straightforward and in younger patients 1.
From the FDA Drug Label
Wilson's disease (hepatolenticular degeneration) occurs in individuals who have inherited an autosomal-recessive defect that leads to an accumulation of copper far in excess of metabolic requirements Wilson's disease (hepatolenticular degeneration)is an autosomal inherited metabolic defect resulting in an inability to maintain a near-zero balance of copper. Wilson's disease (hepatolenticular degeneration) is an autosomal recessive metabolic defect in hepatic excretion of copper in the bile, resulting in accumulation of excess copper in the liver, and subsequently in other organs, including the brain, kidneys, eyes, bone, and muscles
The pathophysiology of Wilson disease is characterized by an autosomal-recessive defect that leads to an accumulation of excess copper in the body. This excess copper is deposited in several organs and tissues, including the liver and brain, causing pathological effects. The defect results from an inability to maintain a near-zero balance of copper and an inability to excrete free copper into the bile. As a result, hepatocytes store excess copper, but when their capacity is exceeded, copper is released into the blood and taken up into extrahepatic sites, leading to motor disorders, psychiatric manifestations, and hepatocellular injury 2, 3, 4.
- Key features of the pathophysiology of Wilson disease include:
- Accumulation of excess copper in the body
- Deposition of copper in organs and tissues, including the liver and brain
- Inability to maintain a near-zero balance of copper
- Inability to excrete free copper into the bile
- Hepatocellular injury and motor disorders
- Psychiatric manifestations
- The main organs affected by Wilson disease are the liver and brain.
From the Research
Pathophysiology of Wilson Disease
The pathophysiology of Wilson disease is characterized by a genetic disorder of copper metabolism, leading to the accumulation of copper in the liver, brain, and other organs 5, 6, 7, 8. This accumulation is due to mutations in the ATP7B gene, which encodes a transmembrane copper-transporting ATPase, resulting in impaired copper homeostasis and copper overload 8.
Key Features of Wilson Disease
- Accumulation of copper in the liver, brain, and other organs due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein 7
- Generation of reactive oxygen species (ROS) and cuproptosis, leading to copper-dependent cell death 7
- Increased iron deposits in the liver, leading to iron-related ferroptosis and phospholipid peroxidation within membranes of subcellular organelles 7
- Multifaceted clinical features, including depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser-Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia 7
Diagnostic and Therapeutic Issues
- Diagnosis requires a combination of clinical signs and symptoms, as well as diagnostic tests such as the measurement of serum ceruloplasmin, urinary excretion of copper, liver biopsy, or genetic testing 5, 6, 8
- Treatment includes copper chelating agents, such as d-Penicillamine, trientine, and zinc salts, which must be maintained lifelong 5, 6, 8
- Liver transplantation is an option for patients with end-stage liver disease or acute liver failure 5, 6, 8
Recent Advances in Treatment
- Gene therapy with recombinant adeno-associated vectors (AAV) holds promise for Wilson disease treatment, with the use of split intein technology to drive the reconstitution of full-length human ATP7B protein 9
- New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models 8