Wilson disease follows a single fault: loss of function of ATP7B, the copper-transporting ATPase that hepatocytes use both to load ceruloplasmin with copper and to send surplus copper into bile. Without it, copper cannot leave the liver cell, and the damage begins there.
The gene and its inheritance
The ATP7B gene lies on chromosome 13 and encodes the Wilson ATPase, a membrane-bound copper transporter of the P-type ATPase family. The protein is built from several motifs: 6 metal-binding domains, 8 transmembrane domains that form the channel through which copper passes, an ATP-binding domain that powers the transport, and an actuator domain that regulates it.
The disease is inherited in an autosomal recessive pattern, so a person must carry a pathogenic variant on each copy of the gene to be affected. It affects roughly 30 people per million, or about 1 in 30,000, and most patients are compound heterozygotes, with a different variant on each allele. No reliable relationship between the type of variant and the clinical picture has been established, so the same genetic defect can produce liver disease in one patient and neurological disease in another. Each sibling of an affected person has a 1 in 4 chance of being affected and a 1 in 2 chance of being a carrier, which is why relatives are offered testing.
What the mutation does in the hepatocyte
In health, ATP7B has two jobs inside the hepatocyte. It loads copper onto apoceruloplasmin to make holoceruloplasmin, the copper-carrying form, and it pumps excess copper into bile. When ATP7B is mutated, both jobs fail, so copper is retained inside the hepatocyte and accumulates.
The cell first tries to contain the load. In the early stages, intracellular copper is chelated by metallothionein, an intracellular binding protein, so the copper is held in a non-toxic form and staining of the hepatocytes is negative for copper. Once the copper over-accumulates beyond the capacity of metallothionein, it is deposited inside the lysosomes, and from that point staining for copper becomes positive.
The liver under the microscope
Before cirrhosis develops, the pathological findings are steatosis, focal necrosis and glycogenated nuclei in hepatocytes, together with mitochondrial changes best appreciated on electron microscopy. The mitochondria vary in size, and the space between their inner and outer membranes widens, dilating the tips of the cristae into a finding called tennis-like cristae. This is not specific to Wilson disease, but in a young patient with suspected disease it is highly suggestive. With continued injury, fibrosis follows and the liver becomes cirrhotic, usually in a macronodular pattern.