Wilson's Disease
A Gastroenterology Perspective

Presentation of Wilson's Disease

Liver disease is always present when a Wilson's Disease patient presents with any symptoms. Some present with fulminant hepatic failure and others with only one abnormal liver function test.
Whenever there is any abnormality of the liver, including cirrhosis and chronic hepatitis (which is not completely explained by a particular diagnosis), Wilson's Disease should be considered by determining blood ceruloplasmin and 24-hour urinary copper excretion levels.
Liver-related symptoms and signs such as ascites, fatigue, loss of appetite, weakness, and weight loss or gain may also be presenting findings.
Other presenting signs are motor disturbances such as tremors, difficulty walking, talking, writing, and swallowing, the full gamut of psychiatric conditions, nonimmune hemolytic anemia, renal disturbances with increased calcium and uric acid excretion, tubular dysfunction, amenorrhea, and spontaneous abortion.

Copper Metabolism

• Traces of essential copper are absorbed in the small intestine and transported by albumin to the liver, where the hepatocyte incorporates them. Only a trace is excreted in the urine normally. In the hepatocyte, copper binds to glutathione and metallothionein. Copper also plays a role in some enzymes and cofactors as well as ceruloplasmin. Its intracellular site may be in the Golgi apparatus. Excretion into bile, from which it is negligibly reabsorbed, involves the canalicular membrane, lysosomes, and alternatively copper glutathione excretion. Decreased biliary excretion of copper is the fundamental cause of copper accumulation and Wilsonian pathology. Copper accumulation to toxic levels decreases cellular glutathione, changes protein synthesis, and promotes lipid peroxidation.

Diagnostic Tests

Diagnostic tests include:

• 24- hour urine copper levels greater than 100 µg/24 hours
• Serum ceruloplasmin depression to less than 20 mg %
• 20% of heterozygotes (carriers) also have low ceruloplasmin levels
• Kayser-Fleischer rings are invariably present with neurologic or psychiatric symptoms. A slit-lamp exam is required to confirm their presence.
• Liver biopsy revealing greater than 250 µg/g dry weight of copper. There are also characteristic microscopic changes including glycogen nuclei, microvesicular and macrovesicular fatty changes, steatosis, and fibrosis. Fulminant Wilsonian hepatitis results in Mallory bodies and submassive necrosis.

Cytochemical testing results with rhodanine, rubeanic acid, orcein, and Victoria blue are significant only when positive. The electron microscope shows characteristic mitochondrial changes with pleiotropism, increased matrix density, matrical inclusion, widening of intermembranous and intracristal spaces. Less specific changes include lysosomal density due to copper accumulation.

Genetic Diagnosis

Because of the many possible mutations involved in Wilson's disease, molecular genetic diagnosis is beneficial primarily in families where the particular gene responsible is known.

Therapy Overview

Wilson's disease is a very treatable condition. With proper drug therapy, disease progression can be halted, and often symptoms can be improved. The treatment goal is to first remove the excess accumulated copper in the body and then to prevent its reaccumulation. Therapy must be lifelong.

Galzin (zinc acetate) capsules are indicated for maintenance therapy in patients who have undergone initial treatment with a chelating agent. Galzin works by a different mechanism of action from chelating agents, it blocks absorption of copper from the intestine. In addition, Galzin has a different safety profile from chelating therapies.

Clinical experience with zinc acetate has been limited. The following adverse reactions have been reported in patients with Wilson's disease on zinc therapy: gastric irritation, and elevations of serum alkaline phosphatase, amylase and lipase lasting from weeks to months. The levels usually return to high normal within the first year or two of zinc therapy.

Other drugs approved for use in Wilson's disease act by chelation or binding of copper, causing its increased urinary excretion. Other therapies are under investigation for initial treatment of Wilson's disease in the hope that they will not cause worsening of neurologic symptoms, as may occur with penicillamine. Patients with severe hepatitis may require liver transplant.
Whichever treatment strategy is chosen, physicians and their Wilson's disease patients must keep in mind that continued compliance with therapy is essential. Discontinuation of treatment will lead to recurrence and worsening of Wilson's Disease symptoms.