WILSON DISEASE

DEFINITION
Wilson's disease (WD) is an inborn error of copper metabolism characterized by excessive copper deposition, predominantly in the liver and brain [169].
DIAGNOSTIC CONSIDERATIONS [170]

• Characterized by excessive deposition of copper in the liver and brain.
• Rare autosomal recessive disorder that usually occurs between the first and third decades.
• Serum ceruloplasmin, the plasma copper-carrying protein, is low.
• Urinary excretion of copper and hepatic copper concentration are high.
EPIDEMIOLOGY

WD is present in most populations worldwide, and particularly in those in which consanguineous marriage is common. The disease frequency is estimated to be between 1 in 5,000 and 1 in 30,000, and the carrier frequency is approximately 1 in 90 [169,171].
Sex:
The fulminant presentation of Wilson disease is more common in females than 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.


CAUSE

The genetic defect, localized to chromosome 13, has been shown to affect a copper-transporting adenosine triphosphatase (ATP7B) in the liver and leads to copper accumulation in the liver and oxidative damage of hepatic mitochondria [172]

CLINICAL FEATURES

The clinical presentation of Wilson's disease is variable, depending in part upon age.
• Clinical manifestations of Wilson's disease are rare before age 6 and almost always present before the age of 30, although it has been described in those as young as age 3 and patients presenting in their seventies [173,174].
• Adolescents tend to present with liver disease while young adults are more likely to present with neuropsychiatric disease [175]. All patients with neuropsychiatric disease have compensated cirrhosis which is often not detected until Wilson's disease is diagnosed.
• Consider hepatic Wilson disease in the differential diagnosis of any unexplained chronic liver disease, especially in individuals younger than 40 years

Hepatic disease
There are several different syndromes associated with hepatic copper accumulation in Wilson's disease [169]
• Chronic hepatitis
• Asymptomatic liver function abnormalities
• Portal hypertension
• Fulminant hepatic failure
Most patients with the fulminant hepatic failure presentation of WD have a characteristic pattern of clinical and biochemical findings:

1. Coombs-negative hemolytic anemia with features of acute intravascular hemolysis
2. Coagulopathy unresponsive to parenteral vitamin K administration
3. Rapid progression to renal failure
4. Relatively modest rises in serum aminotransferases (typically <2,000 IU/L) from the beginning of clinical illness
5. Normal or markedly subnormal serum alkaline phosphatase (typically <40 IU/L)
6. Female to male ratio of 2:1

Neuropsychiatric disease
o Most patients who present with neuropsychiatric manifestations have cirrhosis [176].
o 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.
o Frequent early symptoms include difficulty speaking, excessive salivation, ataxia, masklike facies, clumsiness with the hands, and personality changes.
o Late manifestations (now rare because of earlier diagnosis and treatment) include dystonia, spasticity, grand mal seizures, rigidity, and flexion contractures.
o One study describes 4 distinct diagnostic categories based on patients' major neurologic finding [177].
 The parkinsonian patients (45%) were distinguished by paucity of expression and movement.
 The pseudosclerotic patients (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.
o 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