
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.14 Free copper can lead to toxic effects, so regulating copper balance in the body is vital.14
Dietary copper is absorbed from the proximal small intestine and transported into the liver.3 Copper is normally transported in the blood in a variety of forms:
- The majority of copper (65−71%) in the blood is bound to ceruloplasmin (a protein involved in iron metabolism)14
- A smaller fraction is either bound to albumin (15−19%) or transcuprein (7−15%) for transport (referred to as exchangeable or labile copper)14
- A tiny fraction of copper (<2−5%) in the blood is “free” copper and an excess of this fraction is believed to be what causes toxicity in Wilson disease4,14
In order to maintain a normal copper balance, excess copper must be excreted. The main route of copper excretion is in the bile, which is mediated by the copper transporter ATP7B.15,16 ATP7B also plays a role in the incorporation of copper into apoceruloplasmin in the liver for transport around the body.3
In Wilson disease, mutations in the ATP7B gene and reduced ATP7B activity in the liver lead to reduced copper excretion in the bile and reduced ceruloplasmin synthesis, and increased urinary copper excretion in an attempt to compensate.13,16 Copper builds up and eventually spills out from the liver and is deposited in other organs and tissues.3,15 This accumulation of toxic free copper leads to cellular damage and the clinical Wilson disease phenotype.3,15,16