Wilson Disease 

Wilson disease is a rare autosomal recessive inherited disorder of copper metabolism. The condition is characterized by excessive deposition of copper in the liver, brain, and other tissues. The major physiologic aberration is excessive absorption of copper from the small intestine and decreased excretion of copper by the liver. (See Etiology.)

The genetic defect, localized to arm 13q, has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Patients with Wilson disease more often initially present with hepatic manifestations when identified in the first decade of life as compared with more neuropsychiatric illness later, and the latter most commonly occurs during the third decade. The diagnosis is established by no individual test but requires the use of some combination of serum ceruloplasmin level, urinary copper excretion, presence of Kayser-Fleischer rings, and hepatic copper content when biopsy is required. (See Etiology, Clinical, and Workup.)

Although it is extremely rare in clinical practice, Wilson disease is important because it is often fatal if not recognized and treated when symptomatic. Often, the diagnosis is not made until adulthood, despite manifestations of the disease beginning to develop in childhood. (See Differentials, Treatment, and Medications.)

Staging

The natural history of Wilson disease may be considered in 4 stages, as follows:

• Stage I - The initial period of accumulation of copper within hepatic binding sites
• Stage II - The acute redistribution of copper within the liver and its release into the circulation
• Stage III - The chronic accumulation of copper in the brain and other extrahepatic tissue, with progressive and eventually fatal disease
• Stage IV - Restoration of copper balance by the use of long-term chelation therapy

Patient education

For patient education information, see the Digestive Disorders Center, as well as Cirrhosis.

The normal estimated total body copper content is 50-100 mg, and the average daily intake 2-5 mg, depending on an individual’s intake of legumes, meats, shellfish, and chocolate. Copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase.

Around 50-75% of intestinal copper is absorbed and then transported to the hepatocytes. This pathway is intact in Wilson disease. After copper reaches the hepatocyte, it is incorporated into copper-containing enzymes and copper-binding proteins (CBPs), including ceruloplasmin, a serum ferroxidase. Within the liver, the majority of in-infancy (< 6 mo) CBP granules staining positive may be normal. After 6 months, positive staining of CBPs for copper is almost exclusively found in association with liver diseases such as Wilson disease, chronic biliary disorders (eg, primary biliary cirrhosis, primary sclerosing cholangitis), cirrhosis/extensive fibrosis, and primary liver tumors (most often fibrolamellar hepatocellular carcinoma).

Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted into bile. Normal copper balance is maintained by regulation of excretion, rather than absorption, and the predominant route of copper excretion (approximately 95%) is hepatobiliary in nature.

In Wilson disease, the processes of incorporation of copper into ceruloplasmin and excretion of excess copper into bile are impaired.^[1] The transport of copper by the copper-transporting P-type ATPase is defective in Wilson disease secondary to one of several mutations in the ATP7B gene. By genetic linkage studies, Bowcock and colleagues narrowed the assignment of the Wilson disease locus to 13q14-q21.^[2]

Many of the gene defects for ATP7B are small deletions, insertions, or missense mutations. Most patients carry different mutations on each of their 2 chromosomes. More than 40 different mutations have been identified, the most common of which is a change from a histidine to a glutamine (H1069Q). Stapelbroek et al linked the H1069Q mutation to a late and neurologic presentation.^[3]

The excess copper resulting from Wilson disease promotes free radical formation that results in oxidation of lipids and proteins. Ultrastructural abnormalities in the earliest stages of hepatocellular injury, involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei, have been identified. Initially, the excess copper accumulates in the liver, leading to damage to hepatocytes. Eventually, as liver copper levels increase, it increases in the circulation and is deposited in other organs.

Stuehler et al reported that base pair changes in the MURR1 gene were associated with an earlier presentation of Wilson disease.^[4] MURR1 had previously been established to cause canine copper toxicosis in Bedlington terriers.

In the United States, the carrier frequency is 1 per 90 individuals. The prevalence of Wilson disease is 1 per 30,000 individuals.

Worldwide, the incidence of Wilson disease is 10-30 million cases, and the heterozygote carrier rate is 1 case per 100 persons, with the genetic mutation frequency varying from 0.3-0.7%. In Japan, the rate is 1 case per 30,000 population, compared with 1 case per 100,000 population in Australia. The increased frequency in certain countries is due to high rates of consanguinity. The fulminant presentation of Wilson disease is more common in females than in males.

Age-related presentations

A German study of patients with Wilson disease illustrated that patients presenting earlier show predominantly hepatic symptoms (15.5 [9.6] y), while those presenting later more often present with neurological symptoms (20.2 [10.8] y).^[5]

Thomas and colleagues reviewed the mutations found in the ATP7B gene, and their findings suggested a wide age span in the onset of Wilson disease, perhaps wider than previously considered typical. Mutations that completely disrupt the gene can produce liver disease in early childhood, at a time when Wilson disease may not be considered in the differential diagnosis.^[6]

In general, the upper age limit for considering Wilson Disease is 40 years and the lower age limit is 5 years, although the disorder has been detected in children younger than 3 years and in adults older than 70 years.^[7]

Patients with a prognostic index (ie, score) of 7 or greater should be considered for liver transplantation (see Table 1, below). All patients in the study associated with this prognostic index who exceeded this score died within 2 months of diagnosis, irrespective of the institution of appropriate medical therapy.

Table. Prognostic Index in Fulminant Wilsonian Hepatitis (Open Table in a new window)

Prognosis after liver transplantation is relatively good. In a study involving 55 patients with Wilson disease who underwent hepatic transplantation, the 1-year survival rate was 79% and the overall survival rate was 72% at 3 months to 20 years. Another study of 32 patients reported a 1-year survival of 90.6%, a 5-year survival rate of 83.7%, and a 10-year survival rate of 79.9% after living donor liver transplantation.^[8]

Important clues for the diagnosis of Wilson disease that a clinician must recognize are a younger patient with hemolytic anemia, impaired hepatic synthetic function, and normal alkaline phosphatase values.

Complications

The major complications in patients with untreated Wilson disease are those associated with acute liver failure, chronic hepatic dysfunction with either portal hypertension or hepatocellular carcinoma, and the sometimes-relentless course to cirrhosis, which is characterized by a progressive lassitude, fatigue, anorexia, jaundice, spider angiomas, splenomegaly, and ascites. Bleeding from varices, hepatic encephalopathy, hepatorenal syndrome, and coagulation abnormalities occur as liver failure ensues. Death occurs, generally at age 30 years, if emergent liver transplantation is not performed.

Unfortunately, Wilson disease has other systemic consequences of copper overload. Most patients who present with neuropsychiatric manifestations have cirrhosis. The reported percentage of patients with psychiatric symptoms as the presenting clinical feature is 10-20%. The range of psychiatric abnormalities associated with Wilson disease extends from behavioral/mood state disturbances through movement disorders (occasionally choreoathetoid) or parkinsonian features. These features, on occasion, can be made worse with chelation therapy.