Wilson disease results in accumulation of copper in the liver and other organs. Hepatic or neurologic symptoms develop. Diagnosis is based on a low serum ceruloplasmin level, high urinary excretion of copper, and sometimes liver biopsy results. Treatment consists of a low-copper diet and drugs such as penicillamine or trientine.
Wilson disease is a disorder of copper metabolism that affects men and women; about 1 person in 30,000 has the disorder. Affected people are homozygous for the mutant recessive gene, located on chromosome 13. Heterozygous carriers, who constitute about 1.1% of the population, are asymptomatic.
Pathophysiology
The genetic defect in Wilson disease impairs copper transport. The impaired transport decreases copper secretion into the bile, thus causing the copper overload and resultant accumulation in the liver, which begins at birth. The impaired transport also interferes with incorporation of copper into the copper protein ceruloplasmin, thus decreasing serum levels of ceruloplasmin.
Hepatic fibrosis develops, ultimately causing cirrhosis. Copper diffuses out of the liver into the blood, then into other tissues. It is most destructive to the brain but also damages the kidneys and reproductive organs and causes hemolytic anemia. Some copper is deposited around the rim of the cornea and edge of the iris, causing Kayser-Fleischer rings. The rings appear to encircle the iris.
Symptoms and Signs
Symptoms of Wilson disease usually develop between ages 5 and 35 but can develop from age 2 to 72 yr.
• In almost half of patients, particularly adolescents, the first symptom is Hepatitis—acute, chronic active, or fulminant. But hepatitis may develop at any time.
• In about 40% of patients, particularly young adults, the first symptoms reflect CNS involvement.
Motor deficits are common, including any combination of tremors, dystonia, dysarthria, dysphagia, chorea, drooling, and incoordination. Sometimes the CNS symptoms are cognitive or psychiatric abnormalities.
In 5 to 10% of patients, the first symptom is incidentally noted gold or greenish gold Kayser-Fleischer rings or crescents (due to copper deposits in the cornea), amenorrhea or repeated miscarriages, or hematuria.
Diagnosis
• Slit-lamp examination for Kayser-Fleischer rings
• Serum ceruloplasmin and 24-h urinary copper excretion
• Sometimes confirmation by penicillamine provocation test or liver biopsy
Wilson disease should be suspected in people < 40 with any of the following:
An unexplained hepatic, neurologic, or psychiatric disorder
An unexplained persistent elevation in hepatic transaminases
A sibling, parent, or cousin with Wilson disease
Fulminant hepatitis
If Wilson disease is suspected, slit-lamp examination for Kayser-Fleischer rings is required, and serum ceruloplasmin and copper levels and 24-h urinary copper excretion are measured. Transaminase levels are also often measured; high levels are consistent with the diagnosis.
Kayser-Fleischer rings
These rings plus typical motor neurologic abnormalities or a decrease in ceruloplasmin are nearly pathognomonic for Wilson disease. Rarely, these rings occur in other liver disorders (eg, biliary atresia, primary biliary cirrhosis), but ceruloplasmin levels should be unaffected.
Ceruloplasmin
Serum ceruloplasmin (normally 20 to 35 mg/dL) is usually low in Wilson disease but can be normal. It can also be low in heterozygous carriers and those with other liver disorders (eg, viral hepatitis, drug- or alcohol-induced liver disease). A low ceruloplasmin level in a patient with a Kayser-Fleischer ring is diagnostic. Also, a level of < 5 mg/dL is highly suggestive regardless of clinical findings.
Serum copper
Serum copper levels may be high, normal, or low.
Urinary copper excretion
In Wilson disease, 24-h urinary copper excretion (normally, ≤ 30 μg/day) is usually > 100 μg/day. If serum ceruloplasmin is low and urinary copper excretion is high, diagnosis is clear. If levels are equivocal, measuring urinary copper excretion after penicillamine is given (penicillamine provocation test) may confirm the diagnosis; this test is not usually done in adults because cutoff values are not well-established.
Liver biopsy
In unclear cases (eg, elevated transaminases, no Kayser-Fleischer rings, indeterminate values for ceruloplasmin and urinary copper), the diagnosis is made by doing a liver biopsy to measure hepatic copper concentration. However, false-negative results may occur because of a sampling error (due to large variations in copper concentrations in the liver) or fulminant hepatitis (causing necrosis that releases large amounts of copper).
Screening for Wilson disease
Because early treatment is most effective, screening is indicated for anyone who has a sibling, cousin, or parent with Wilson disease. Screening consists of a slit-lamp examination and measurement of transaminase levels, serum copper and ceruloplasmin, and 24-h urine copper excretion. If any results are abnormal, liver biopsy is done to measure hepatic copper concentration. Infants should not be tested until after age 1 yr because ceruloplasmin levels are low during the first few months of life. Children < 6 yr with normal test results should be retested 5 to 10 yr later.
Prognosis
Prognosis for patients with Wilson disease is usually good, unless disease is advanced before treatment begins. Untreated Wilson disease is fatal, usually by age 30.
Treatment
• Penicillamine or trientine
• Low-copper diet
• For maintenance, lifelong low-dose penicillamine or trientine, or oral zinc
Continual, lifelong treatment of Wilson disease is mandatory regardless of whether symptoms are present. A low-copper diet (eg, avoiding beef liver, cashews, black-eyed peas, vegetable juice, shellfish, mushrooms, and cocoa) and use of penicillamine, trientine, and sometimes oral zinc can prevent copper from accumulating. Copper content in drinking water should be checked, and people should be advised not to take any vitamin or mineral supplements containing copper.
Penicillamine is the most commonly used chelating drug but has considerable toxicity (eg, fever, rash, neutropenia, thrombocytopenia, proteinuria). Cross-reactivity may occur in people with penicillin allergy. Patients > 5 yr are given oral doses of 62.5 mg q 6 h to 250 mg q 12 h (250 to 500 mg/day in 2 to 4 doses) and slowly increased to a maximum of 250 mg q 6 h to 750 mg q 12 h (1000 to 1500 mg/day in 2 to 4 doses). Younger children are given 10 mg/kg bid or 6.7 mg/kg tid (20 mg/kg/day) po. Pyridoxine 25 mg po once/day is given with penicillamine. Occasionally, use of penicillamine is associated with worsening neurologic symptoms.
Trientine hydrochloride is an alternative treatment to penicillamine. Doses are 375 to 750 mg po bid or 250 to 500 mg po tid (750 to 1500 mg/day).
Zinc acetate 50 mg po tid can reduce intestinal copper absorption, thus preventing reaccumulation of copper in patients who cannot tolerate penicillamine or trientine or who have neurologic symptoms that do not respond to the other drugs. (Caution: Penicillamine or trientine must not be taken at the same time as zinc because either drug can bind zinc, forming a compound with no therapeutic effect.)
Poor long-term adherence to drug therapy is common. After 1 to 5 yr of therapy, lower dose maintenance drug therapy can be considered. Regular follow-up care with an expert in liver disease is recommended.
Liver transplantation may be lifesaving for patients who have Wilson disease and fulminant hepatic failure or severe hepatic insufficiency refractory to drugs.
Key Points
• Wilson disease is a rare, autosomal recessive disorder in which copper accumulates in various organs.
• The disease manifests during childhood or adulthood, usually between ages 5 and 35.
• Suspect the disorder in people with a family history of the disorder or unexplained hepatic, neurologic, or psychiatric abnormalities (including elevated transaminase levels).
• Confirm the diagnosis primarily with a slit-lamp examination (for Kayser-Fleischer rings) and measurement of serum ceruloplasmin (which is low) and 24-h urinary copper excretion (which is high).
• Advise patients to follow a low copper diet, and treat them with penicillamine, trientine, or, if these drugs are intolerable or ineffective, oral zinc.
CLINICAL VIGNETTES
A 29-year-old man suffered from hepatitis, splenomegaly, a Coombs-negative hemolytic anemia, and portal hypertension during his adolescent and earlier adult years. Now, he is showing signs of behavioral and personality changes with emotional lability. In addition, he has a profound resting tremor, his speech has become slurred and difficult to understand, and he drools and has trouble swallowing. Physical examination shows a rim of brown pigment around the perimeter of the cornea. Which one of the following laboratory findings would most likely be reported?
A) Decreased serum ceruloplasmin
B) Increased serum ferritin
C) Increased serum mitochondrial antibodies
D) Increased total serum copper
E) Normal serum prothrombin time
The answer is A. The patient has Wilson disease, which is an autosomal recessive disease due to genetic aberration in the “Wilson” gene on chromosome 13; the worldwide prevalence is 1 cases per 30,000 persons. More than 200 different mutations have been uncovered, leading to some variation in symptoms. However, typically, the disease first presents in adolescence with liver disease plus a variety of hemolytic and other symptoms, then progresses in early adulthood to neurologic problems similar to those described. Once the disease progresses to the neurologic state, a Kayser-Fleischer ring (brown pigment around the perimeter of the cornea) is essentially pathognomic for the condition. The genetic defect affects a copper-transporting ATPase (ATP7B) in the liver and leads to accumulation of copper in the hepatocytes and oxidative damage to hepatic mitochondria. The major physiologic effects are due to a defect in the hepatocyte transport system for copper secretion into bile, leading to increased copper deposition in liver, brain, cornea, and kidneys. In addition, copper cannot be incorporated into an 2-globulin to produce ceruloplasmin, which is the copper-binding protein.
Normally, the total serum copper equals copper that is bound to ceruloplasmin (95% of the total) plus copper that is unbound (free). In Wilson disease, the total serum copper level is decreased (not increased [choice D]) because ceruloplasmin is decreased (choice A). However, the free copper level in the serum and urine is increased because of defective excretion in the bile and subsequent accumulation of copper in the serum. Excess copper is deposited in Descemet’s membrane of the cornea of the eye (producing Kayser-Fleischer ring) and in the basal ganglia. In the latter location, it may cause parkinsonism, choreiform movements, and dystonia in the bulbar musculature. This latter effect can produce dysarthria (problems with speech and/or drooling) and/or dysphagia. Increased serum ferritin (choice B) in the setting of chronic liver disease is associated with hemochromatosis, an autosomal recessive disease with unrestricted reabsorption of iron from the gastrointestinal tract.
Hemochromatosis is not associated with corneal abnormalities or a movement disorder. Increased serum mitochondrial antibodies (choice C) is a marker for primary biliary cirrhosis, an autoimmune disease characterized by destruction of bile ducts in the portal triads. It is not associated with corneal abnormalities or a movement disorder. Since the patient has chronic liver disease (chronic hepatitis or cirrhosis), the prothrombin time is most likely increased (not normal [choice E]) because of decreased synthesis of coagulation factors in the damaged liver.
A 13-year-old girl is brought to pediatrician because her mother says “she just sits around.” Physical examination reveals akinesia and rigidity without other obvious neurologic deficits. Her eyes are unusual, with thin greenish-brown rings around the outer edge of the cornea. Serum liver
enzymes are moderately elevated. Which of the following medications would likely be most effective in treating this patient?
A. Deferoxamine
B. Edetate (EDTA)
C. Lithium
D. Penicillamine
E. Phenobarbital
The correct answer is D. The disease is Wilson’s disease. This is an autosomal recessive abnormality of copper metabolism that can present with either neurologic (psychiatric symptoms, bradykinesia and rigidity, tremors, or chorea) or hepatic (hepatitis, cirrhosis, or asymptomatic liver function test abnormalities) findings. The corneal rings described in the question stem are the pathognomic Kayser-Fleischer rings due to copper deposition. Treatment is with life-long administration of the copper-chelating agent, penicillamine.
Deferoxamine (choice A) is used parenterally to chelate circulating iron. EDTA (choice B) is an effective chelator of divalent (and trivalent) cations such as lead. It is administered as the Na2CaEDTA salt to avoid hypocalcemia. Lithium (choice C) is used to treat bipolar disorder. Phenobarbital (choice E) is used to treat epilepsy.