Chapter 17 Wilson disease and related disorders
Fig. 17.1 Copper (Cu) absorption and excretion. Dietary copper (1 to 2 mg/day) is transported into the intestinal epithelial cell, with the Menkes gene product regulating absorption (25% to 60%). The remaining intraepithelial copper is bound to metallothionein and is subsequently excreted in stool as the intestinal epithelial cells are sloughed. A small amount of the absorbed copper is excreted in urine, but the majority is taken up by the hepatocyte, synthesized into ceruloplasmin, and stored in the liver or excreted in bile.
Fig. 17.2 Hepatocellular copper metabolism. Copper (Cu) is taken up by hepatocytes, where it interacts with glutathione and metallothionein. A portion of the intracellular copper is incorporated into metalloenzymes (e.g., superoxide dismutase, cytocrome cxidose), and some is transported into the trans-Golgi network by the WD gene protein (ATP7B), where it is incorporated into ceruloplasmin. It is postulated that copper is also routed from the trans-Golgi apparatus to a vesicular compartment in lysosomes for subsequent excretion in bile. Copper bound to glutathione is also excreted into the bile canaliculus through the organic anion transporter (cMOAT or MRP2) or by direct interaction with a postulated adenosine triphosphate (ATP)–dependent copper transporter.
Patients with WD may be asymptomatic, although most present with hepatic or neurologic manifestations. Clinical symptoms are rarely observed before age 5 years, and most untreated patients become symptomatic by the age of 40 years. In a large series, the initial clinical manifestations were hepatic in 42%, neurologic in 34%, psychiatric in 10%, and hematologic in 12%. A few patients present with WD when they are more than 40 years old, and they normally present with neurologic symptoms that are commonly overlooked. Less commonly, patients present with renal, skeletal, cardiac, ophthalmologic, endocrinologic, or dermatologic symptoms.
Hepatic manifestations tend to occur at a younger age (mean, 10 to 12 years) than neurologic manifestations. Three major patterns may occur: cirrhosis, chronic hepatitis, or fulminant hepatic failure: