The ATP7B gene, located on chromosome 13, encodes a transmembrane copper-transporting ATPase that is expressed on the hepatocyte canalicular membrane. The overwhelming majority of patients with Wilson disease are compound heterozygotes with different loss-of-function mutations affecting each ATP7B allele. The overall frequency of mutated alleles is 1:100, and the prevalence of the disease is approximately 1:30,000 to 1:50,000. Loss of ATP7B protein function impairs the transport of copper into the bile and the incorporation of copper into ceruloplasmin, which is not secreted in its apoceruloplasmin form. These abnormalities lead to copper accumulation in the liver and a decrease in plasma ceruloplasmin. Accumulating copper causes liver injury through the production of reactive oxygen species by the Fenton reaction (Chapter 3). Eventually, non-ceruloplasmin–bound copper is released from injured hepatocytes into the circulation, causing red cell hemolysis and allowing copper to deposit in other tissues, such as the brain, corneas, kidneys, bones, joints, and parathyroid glands. Concomitantly, urinary excretion of copper increases markedly from its normal minuscule levels.
MORPHOLOGYTheliveroftenbearsthebruntofinjury.Thehepaticchangesarevariable,rangingfromrelativelyminortomassiveandmimicmanyotherdiseaseprocesses.Theremaybemildtomoderatefatty change (steatosis) associatedwithfocalhepatocytenecrosis.Acute, fulminant hepatitis canmimicacuteviralhepatitis.Chronic hepatitis inWilsondiseaseexhibitsmoderatetosevereinflammationandhepatocytenecrosis,areasoffattychange,andfeaturesofsteatohepatitis(hepatocyteballooningwithprominentMallory-Denkbodies).Inadvancedcases,cirrhosis maybeseen.Copperdepositioninhepatocytescanbedemonstratedbyspecialstains(rhodaminestainforcopper,orceinstainforcopper-associatedprotein).
Toxicinjurytothebrainprimarilyaffectsthebasalganglia.NearlyallpatientswithneurologicinvolvementdevelopeyelesionscalledKayser-Fleischer rings, greentobrowndepositsofcopperinDesçemetmembraneinthelimbusofthecornea.
The age at onset and the clinical presentation of Wilson disease are extremely variable. Symptoms usually appear between 6 and 40 years of age. Acute or chronic liver disease are common presenting features. Neuropsychiatric manifestations are the initial features in most of the remaining cases and stem from deposition of copper in the basal ganglia.
The diagnosis of Wilson disease is based on low levels of serum ceruloplasmin, an increase in hepatic copper content (the most sensitive test), and increased urinary excretion of copper (the most specific test). Hepatic copper content in excess of 250 µg per gram dry weight of liver is taken to be diagnostic, but is only about 80% sensitive. In those with lower liver copper levels, the diagnosis depends on other abnormalities, such as elevated urinary copper, low serum ceruloplasmin, and the presence of Kayser-Fleischer rings. Unlike hereditary hemochromatosis, where the limited number of genetic variants makes genetic testing fairly simple, the large number of different causative mutations in ATP7B7 complicates the use of DNA sequencing as a diagnostic test. Serum copper levels also are of no diagnostic value, as they may be low, normal, or elevated, depending on the stage of the liver disease.