Wilson’s Disease is a rare, inherited disorder that disrupts the body’s copper metabolism, leading to a toxic overload of the metal in various organs. The condition is characterized by an abnormal accumulation of copper, primarily in the liver and brain, causing progressive tissue damage. A diagnostic feature is the significantly low level of ceruloplasmin in the blood, which is the main copper carrier. This article explains the molecular failure linking the genetic defect to these low ceruloplasmin levels.
The Essential Functions of Ceruloplasmin
Ceruloplasmin (Cp) is a copper-containing protein synthesized predominantly by the liver, transporting over 95% of copper through the bloodstream. Secreted into the plasma, it functions as a multi-copper oxidase, an enzyme requiring copper atoms to be active. A healthy ceruloplasmin molecule typically binds six copper atoms, forming the stable structure known as holo-ceruloplasmin.
This copper-loaded protein plays a dual role in mineral homeostasis, acting as a ferroxidase enzyme. Its most notable action is oxidizing ferrous iron (Fe2+) into ferric iron (Fe3+) before it is loaded onto the transport protein transferrin. This oxidation is necessary for iron mobilization and transport out of storage cells. The copper atoms are essential for both the protein’s stability and its function in regulating iron metabolism.
The Genetic Root of Wilson’s Disease
The underlying cause of Wilson’s Disease is a mutation in the ATP7B gene on chromosome 13. This gene provides instructions for the copper-transporting ATPase 2 protein. ATP7B is a P-type ATPase that uses energy from adenosine triphosphate (ATP) to move copper across cellular membranes.
In a healthy liver cell, the ATP7B protein is positioned within the Golgi apparatus, an organelle that processes and packages proteins. Its primary function is managing copper levels within the hepatocyte. It performs two tasks: moving copper for incorporation into ceruloplasmin for secretion, and transporting excess copper into the bile for excretion.
When the ATP7B gene is mutated, the resulting protein is non-functional or severely impaired. This defect prevents the liver cell from performing its normal copper-handling duties. The failure to excrete excess copper into the bile leads to toxic accumulation within the liver cells. The defective ATP7B protein also fails its role in ceruloplasmin synthesis, causing the low blood levels characteristic of the disease.
Failed Copper Incorporation and Ceruloplasmin Degradation
The liver continuously produces the ceruloplasmin protein structure, initially without copper, known as apo-ceruloplasmin. To become the stable, functional holo-ceruloplasmin secreted into the blood, it must incorporate six copper atoms within the Golgi apparatus.
The functional ATP7B transporter moves copper into the Golgi lumen, where it is inserted into the newly synthesized apo-ceruloplasmin. In Wilson’s Disease, the defective ATP7B protein cannot efficiently deliver copper into the Golgi apparatus. Consequently, the copper insertion process stalls, and the apo-ceruloplasmin remains copper-free.
The copper-free apo-ceruloplasmin is structurally unstable. Lacking stabilizing copper atoms, the cell’s quality control mechanisms recognize this unstable form as defective. The hepatocyte then rapidly degrades the copper-free apo-ceruloplasmin before it can be released into the bloodstream. This intracellular degradation is the direct molecular reason for the low measured serum ceruloplasmin levels in most Wilson’s Disease patients.
Clinical Manifestations of Copper Toxicity
The failure of the ATP7B transporter to excrete copper into the bile causes progressive accumulation of the metal, primarily in the liver. This buildup leads to chronic inflammation, which can progress to hepatitis, fibrosis, and ultimately liver cirrhosis or acute liver failure. The damage often begins silently, years before outward symptoms appear.
As the liver’s capacity to store the metal is overwhelmed, accumulated copper “spills” out of the damaged liver cells into the systemic circulation. This non-ceruloplasmin-bound, or “free,” copper is highly toxic because it generates damaging reactive oxygen species. This toxic copper travels through the bloodstream and deposits in other organs, most notably the brain and the eyes.
Copper deposition in the brain’s basal ganglia causes a range of neuropsychiatric symptoms, including tremors, difficulty with coordination, speech problems, and mood changes. A classic sign of copper deposition in the eyes is the formation of Kayser-Fleischer rings. These are brownish-green deposits visible in the cornea.