eMedicine Specialties > Gastroenterology > Systemic Disease

Wilson Disease

Author: Rahil Shah, MD, Consulting Staff, Department of Gastroenterology, University Medical Center
Coauthor(s): Michael H Piper, MD, FACG, FACP, Clinical Assistant Professor, Department of Internal Medicine, Division of Gastroenterology, Wayne State University School of Medicine; Consulting Staff, Digestive Health Associates PLC
Contributor Information and Disclosures

Updated: Aug 25, 2009

Introduction

Background

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.

The genetic defect, localized to chromosome arm 13q, has been shown to affect the copper-transporting adenosine triphosphatase (ATPase) gene (ATP7B) in the liver. Patients with Wilson disease usually present with liver disease during the first decade of life or with neuropsychiatric illness during the third decade. The diagnosis is confirmed by measurement of serum ceruloplasmin, urinary copper excretion, and hepatic copper content, as well as the detection of Kayser-Fleischer rings.

Pathophysiology

The estimated total body copper content is 50-100 mg, with an average daily intake of 1-2 mg. Copper is an important component of several metabolic enzymes, including lysyl oxidase, cytochrome c oxidase, superoxide dismutase, and dopamine beta-hydroxylase. Intestinal copper absorption and transport into hepatocytes is intact in Wilson disease. After copper reaches the hepatocyte, it is incorporated into copper-containing enzymes, including ceruloplasmin. Excess copper may be rendered nontoxic by forming complexes with apo-metallothionein to produce copper-metallothionein, or it may be excreted into bile.

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 The excess copper acts as a promoter of free radical formation and causes oxidation of lipids and proteins. In the earliest stages of hepatocellular injury, ultrastructural abnormalities involving the endoplasmic reticulum, mitochondria, peroxisomes, and nuclei have been identified. Initially, the excess copper is stored in the liver and causes damage to the hepatocytes. Eventually, as liver copper levels increase, it is released into the circulation and deposited in other organs.

Frequency

International

The worldwide incidence rate is 10-30 million cases, with increased rates in areas of consanguinity. The heterozygote carrier rate is 1 case per 100 persons, corresponding to a gene frequency varying between 0.3-0.7%. The frequency ranges worldwide from 1 case per 30,000 population in Japan to 1 case per 100,000 population in Australia. The increased frequency in certain countries is due to high rates of consanguinity.

Mortality/Morbidity

Fulminant Wilson disease leads to rapidly progressive liver failure, encephalopathy, coagulopathy, and, eventually, death if emergent liver transplantation is not performed.

Sex

The fulminant presentation of Wilson disease is more common in females than in males (4:1).

Age

Wilson disease manifests as liver disease in children and adolescents, peaking at ages 10-13 years, and as neuropsychiatric illness in young adults aged 19-20 years.

Thomas and colleagues reviewed the mutations found in the ATP7B gene. Their findings suggest 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.³

Clinical

History

Consider hepatic Wilson disease in the differential diagnosis of any unexplained chronic liver disease, especially in individuals younger than 40 years. The condition may also manifest as acute hepatitis. Hepatic dysfunction is the presenting feature in more than half of patients. The 3 major patterns of hepatic involvement are as follows: (1) chronic active hepatitis, (2) cirrhosis, and (3) fulminant hepatic failure. The most common initial presentation is cirrhosis.

• Neuropsychiatric
  • Most patients who present with neuropsychiatric manifestations have cirrhosis. The most common presenting neurologic feature is asymmetric tremor, occurring in approximately half of individuals with Wilson disease. The character of the tremor is variable and may be predominantly resting, postural, or kinetic.
  • Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes.
  • Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.
  • One study describes 4 distinct diagnostic categories based on patients' major neurologic findings.⁴
    • The patients in the parkinsonian group (45%) were distinguished by paucity of expression and movement.
    • The patients in the pseudosclerotic group (24%) had tremor resembling multiple sclerosis.
    • The patients in the dystonic group (15%) were characterized by hypertonicity associated with abnormal limb movements.
    • The patients in the choreic group (11%) were predominantly characterized by choreoathetoid abnormal movements associated with dystonia.
  • Psychiatric features include emotional lability, impulsiveness, disinhibition, and self-injurious behavior. 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 has been divided into 4 basic categories, as follows:
    • Behavioral
    • Affective
    • Schizophreniclike
    • Cognitive
• Ophthalmologic
  • Kayser-Fleischer rings are formed by the deposition of copper in the Descemet membrane in the limbus of the cornea. The color may range from greenish gold to brown; when well developed, rings may be readily visible to the naked eye or with an ophthalmoscope set at +40. When not visible to the unaided eye, the rings may be identified using slit-lamp examination or gonioscopy.
  • Kayser-Fleischer rings are observed in up to 90% of individuals with symptomatic Wilson disease and are almost invariably present in those with neurologic manifestations.
  • Although Kayser-Fleischer rings are a useful diagnostic sign, they are no longer considered pathognomonic of Wilson disease unless accompanied by neurologic manifestations. They may also be observed in patients with chronic cholestatic disorders, such as partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.
  • Kayser-Fleischer rings consist of electron-dense granules rich in copper and sulfur. The rings form bilaterally, initially appearing at the superior pole of the cornea, then the inferior pole, and, ultimately, circumferentially.
• Musculoskeletal
  • Skeletal involvement is a common feature of Wilson disease, with more than half of patients exhibiting osteopenia on conventional radiologic examination.
  • The arthropathy of Wilson disease is a degenerative process that resembles premature osteoarthritis. Symptomatic joint disease, which occurs in 20-50% of patients, usually arises late in the course of the disease, frequently after age 20 years. The arthropathy generally involves the spine and large appendicular joints, such as knees, wrists, and hips. Osteochondritis dissecans, chondromalacia patellae, and chondrocalcinosis have also been described.
• Hematologic
  • Hemolytic anemia is a recognized but rare (10-15%) complication of the disease.
  • Coombs-negative acute intravascular hemolysis most often occurs as a consequence of oxidative damage to the erythrocytes by the higher copper concentration.
• Renal
  • The Wilson disease gene is expressed in kidney tissue; therefore, any renal manifestations may be primary or secondary to release of copper from the liver.
  • Clinically, patients may resemble those with Fanconi syndrome, demonstrating defective renal acidification and excess renal losses of amino acids, glucose, fructose, galactose, pentose, uric acid, phosphate, and calcium. The frequency of renal manifestations is variable.
  • Urolithiasis, found in up to 16% of patients with Wilson disease, may be the result of hypercalciuria or poor acidification.
  • Hematuria and nephrocalcinosis are reported, and proteinuria and peptiduria can occur both before treatment as part of the disease process and after therapy as adverse effects of D-penicillamine.⁵

Physical

Physical findings are consistent with liver disease, to include jaundice, varices, spider angiomas, and palmar erythema.

Causes

Initially, Wilson postulated that the familial incidence of hepatolenticular degeneration was attributable to environmental factors rather than genetic factors. Nearly a decade later, Hall reported that Wilson disease was more frequent in siblings. In 1953, Bearn discovered an autosomal recessive mode of inheritance confirmed by extended genetic analysis of 30 families. Frydman et al localized the Wilson disease (WD) gene to chromosome 13.

The WD gene product is a 1411 amino acid protein with highest levels of expression in the liver, kidneys, and placenta. The WD gene codes for P-type copper-transporting ATPase, now characterized as ATP7B. 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).

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