
Copper metabolism in Wilson disease
Copper is an essential trace element involved in a wide range of processes, including iron oxidation, cellular respiration, and neurotransmitter biosynthesis.13 Reduced capacity to remove copper can lead to intracellular copper accumulation and harmful effects, so regulating copper balance in the body is vital.1,14,15
Dietary copper is absorbed from the proximal small intestine and transported into the liver.1 Copper is normally transported in the blood in a variety of forms:
- The majority of copper (65−71%) in the blood is tightly bound to ceruloplasmin (a protein also involved in iron metabolism)13
- A smaller fraction is bound to albumin (15−19%), transcuprein (7−15%), or amino acids or small peptides (<2–5%) for transport (referred to as exchangeable or labile-bound copper).13 An excess of this fraction, in which copper is more loosely bound, is believed to facilitate subsequent cellular uptake by the liver and other organs, contributing to the pathology of Wilson disease16
Because the body requires only a small amount of absorbed copper, excess copper must be excreted.2 The main route of copper excretion is in the bile, which is mediated by the copper transporter ATP7B protein.14,15 The ATP7B protein also plays a role in the incorporation of copper into apoceruloplasmin in the liver for transport in the blood throughout the body.1,2
In Wilson disease, mutations in the ATP7B gene and reduced ATP7B protein activity in the liver lead to reduced copper excretion in the bile.14,17 Copper builds up and eventually spills out from the liver, increasing deposition in other organs and tissues and urinary copper excretion.1,2,15 This accumulation of excess copper leads to cellular damage and the various clinical manifestations of Wilson disease.14,15