Definitions and Epidemiology
Wilson’s disease is a human copper storage disease. Wilson’s results in the accumulation of toxic levels of copper in mainly the liver and secondarily in other organs such as the kidneys, brain, and cornea. The disease is caused by a mutation in the ATP7B gene, which codes for a protein that facilitates the incorporation of copper into proteins (such as ceruloplasmin) and also the transportation of copper into vesicles that allow it to be secreted in bile.1 The critical effect of a mutation in ATP7B is diminished copper secretion into bile, which leads to excess copper accumulation in the hepatocyte. The disease related to this defect therefore involves toxicity to the liver with clinical disease that may range from abnormal liver function tests to fulminant hepatic failure and cirrhosis.
Wilson’s is an autosomal recessive disease with an estimated incidence of 1:30,000 live births internationally.2 The most common presentation is in the second decade of life with hepatic or hematologic symptoms (40–60%). The remaining patients present with neurologic (~30%) or psychiatric (10%) symptoms in their third or fourth decade.2
In normal human copper metabolism, the dietary intake and absorption of copper is in excess of physiologic needs. The estimated daily copper requirement for an adult is 1.3–1.7 mg, whereas the normal daily Western copper intake is 2–5 mg of copper.3,4 The estimated efficiency of copper absorption in the stomach and small intestine is approximately 40–60%. Therefore, the amount of copper absorbed by the intestine and retained in the body must be regulated to prevent accumulation of excess copper—which is toxic. The main regulatory system for maintaining copper balance in the body is the excretion of up to 80% of absorbed copper in the bile5,6 (Figure 25–1). Up to 1.2–1.7 mg/day of copper is excreted in the bile daily.6,7 There are also several chemical factors that impair intestinal copper absorption, such as excess zinc or ascorbic acid.8–10
Dietary copper is absorbed into the small intestine epithelial cells where it complexes either to the protein metallothionein or to amino acids for transport into the portal circulation. Metallothionein also forms complexes with zinc and cadmium, though less strongly than copper. Zinc stimulates metallothionein synthesis in the intestinal cell. In doing so, it promotes retention of metallothionein-bound copper in the enterocyte that will then be excreted in the feces when the enterocyte is shed.11 It is on this basis that zinc was postulated to reduce intestinal copper absorption and became a modality of treatment for Wilson’s.
Once in the portal circulation, the copper complexes to albumin or amino acids with only a small fraction remaining “free.” A copper transporter (hCTR) for albumin-bound copper then transports the copper into the hepatocyte.12,13 There it interacts with several proteins that direct the copper to chaperones for incorporation into essential proteins (such as ceruloplasmin, copper/zinc superoxide dismutase, and cytochrome c oxidase), or into lysosomes for biliary excretion.
In 1993, it was discovered that Wilson’s disease was caused by a mutation in the ATP7B gene, on chromosome 13, which resulted in absent or reduced function of a copper–chaperone protein, ATP7B.14 ATP7B is a metal-transporting P-type ATPase, located on the trans-Golgi complex of the hepatocyte.15 The ATP7B protein is necessary for transport of copper into vesicles that form lysosomes for excretion into the bile. It also functions in the incorporation of copper into ceruloplasmin. Ceruloplasmin, a copper-containing globulin, is secreted into the systemic circulation from the liver. The functions of ceruloplasmin include the mobilization of iron from tissues (by oxidizing ferrous iron for transfer into transferrin) and the transport of copper to other tissues. The absence or diminished function of ATP7B results in accumulation of copper in the hepatocyte due to both impaired copper excretion into bile and inability to incorporate copper into ceruloplasmin.14 The production of ceruloplasmin without attached copper (apoceruloplasmin), which has a shorter half-life than ceruloplasmin, results in decreased levels of ceruloplasmin in the blood of Wilson’s patients. It is this dynamic that has made measurement of serum ceruloplasmin the primary screening test for Wilson’s.16
Ultimately, the excess retained copper in the hepatocytes of Wilson’s patients leads to toxic injury to the cell and eventually spillage of copper into the circulation, where it may be deposited in other organs such as the brain, cornea, and kidneys. The relative quantity of copper that overflows into the circulation may be measured by determining the copper content of a 24-hour urine collection. In Wilson’s disease, this value usually will be double normal levels of urinary copper of <40 Âµg of copper/24 hours. This is the basis of 24-hour urine collection as the supporting follow-up diagnostic test to the serum ceruloplasmin level for diagnosing Wilson’s.
The mechanism of toxicity of copper at the cellular level may be a combination of several different copper-sensitive processes that include inhibition of cytosolic enzymes and pro-oxidant effects that damage plasma membrane function and alter oxidative phosphorylation in mitochondria. Evidence of abnormal mitochondrial ultrastructure in hepatocytes of patients with Wilson’s disease supports the theory that mitochondria are one of the affected organelles in copper toxicity.17 There is also evidence to suggest that the mechanism of hepatocyte death in Wilson’s disease is via apoptosis that may explain the typical mild elevation in the transaminases associated with hepatitis in Wilson’s disease.18
One of the challenges of diagnosing Wilson’s disease is the wide spectrum of clinical presentations. Wilson’s patients with hepatic symptoms could present with anything from isolated asymptomatic elevated transaminase levels to liver failure. Wilson’s patients with a neurologic presentation can experience symptoms ranging from declining school performance to frank psychosis (Table 25–1). The youngest patient ever reported to present with liver involvement due to Wilson’s disease was 3 years old; therefore, this disorder is not usually considered on the differential of neonatal or infantile liver disease.19 The most common clinical presentation for Wilson’s disease is a hepatic presentation between 10 and 20 years of age (40–60%). The second most common presentation is with primarily neurologic (34%) or psychiatric (10%) symptoms between the ages of 20–40 years2,20 (Figure 25–2). Occasionally, Wilson’s patients are diagnosed based on the finding of hemolytic anemia.
|System Involved||Signs and Symptoms|
|Hepatic||Asymptomatic elevated AST, ALT|
|Gastrointestinal bleeding secondary to portal hypertension|
|Fulminant hepatic failure with jaundice, lethargy, coagulopathy|
|Deterioration in school work|
|Deterioration in handwriting|
|Lack of motor coordination|
|Hematologic||Coombs-negative hemolytic anemia|
Histogram of age of distribution of initial mode of clinical presentation in children and adolescents with Wilson’s disease. Split vertical bars represent combined clinical presentation (adapted from Ref.44, 3rd ed.).
Although Wilson’s disease always begins with liver involvement, many patients may be asymptomatic and therefore go undiagnosed until they present at 20–30 years of age with advanced hepatic or neurologic disease. The symptoms of Wilson’s disease are rarely apparent before 5 years of age. Siblings of known Wilson’s patients can be diagnosed in the presymptomatic phase of the disease by obtaining a screening ceruloplasmin, 24-hour urine for copper, or genetic testing if the screening is ambiguous.
The pathophysiology of the disease predicates the development of clinical symptoms caused by storage of excess copper in various organs. Initially the excess copper is stored in the liver. Once the liver is saturated, the copper is circulated in a free form (nonceruloplasmin-bound) and begins to accumulate in the central nervous system, cornea, kidneys, and endocrine organs. This progression explains the typical mode of presentation during childhood as hepatic disease. Only about 17% of patients under 10 years of age are found to have neuropsychiatric symptoms at presentation, whereas in patients presenting after 18 years of age, 74% experience neurologic manifestations.2,20 It is usually after 10 years of age that patients may manifest evidence of involvement of the other organ systems such as renal, hematologic, and endocrine (Figure 25–2).
One of the most widely recognized extrahepatic manifestations of Wilson’s disease is the characteristic Kayser–Fleischer (K-F) ring in the ocular cornea21 (Figure 25–3). The K-F ring is a green-brown-colored ring at the edge of the cornea caused by copper accumulation. The appearance of the ring is due to the reflection of light from the copper granules deposited there. The ring is usually present at the superior pole of the cornea first and then may progress to the inferior pole and finally circumferentially. Slit-lamp exam by an ophthalmologist is the best way to determine the presence of K-F rings. The K-F ring has no impact on visual acuity, and treatment with chelation therapy can lead to complete disappearance of the rings. The K-F ring is present in the vast majority of Wilson’s patients who present with neurologic symptoms with few exceptions (about 5%).22 Children with Wilson’s generally present with hepatic symptoms initially, and therefore rarely have K-F rings. It is important to note that K-F rings may also occur in other liver diseases that have reduced biliary excretion; therefore, an isolated finding K-F rings is not pathognomonic of Wilson’s disease. In particular, K-F rings due to secondary copper overload may be seen in primary biliary cirrhosis, intrahepatic cholestasis, or chronic hepatitis.23,24 Another ophthalmologic finding of Wilson’s is deposits of copper in the anterior and posterior lens capsule called a “sunflower cataract.”25 These, too, do not interfere with vision and can resolve with chelation therapy.
Kayser–Fleischer ring. Copper deposited in Descemet’s membrane can form a brown ring at the junction of the cornea with the sclera, encircling the iris. This patient has an intense Kayser–Fleischer ring, seen easily with the naked eye. In many cases, these are more subtle, observable only with a slit lamp microscope. Used with permission from Fauci et al. Harrison’s Principles of Internal Medicine, 17th ed. © 2008 The McGraw-Hill Companies, Inc.
The neuropsychiatric presentation of Wilson’s is the first indication of disease in 40–45% of patients older than 20 years of age.2,20 The youngest patient recorded with neurologic onset was 6 years old.2 The symptoms of neurologic involvement of Wilson’s are usually related to dysfunction of the basal ganglia, cerebellum, and corticospinal and corticobulbar pathways. These symptoms are often motor abnormalities associated with cerebellar or extrapyramidal injury.26 They may include tremor, coordination defects, dystonia, or choreiform movements.27–29 Sensory function and intelligence are generally unaffected in Wilson’s disease. In up to 10–25% of Wilson’s disease patients, the initial manifestation may be a psychiatric disturbance. The symptoms can include dementia, neuroses, schizophrenia, psychosis, or antisocial behavior. It is therefore important for psychiatrists to consider this diagnosis when evaluating psychiatric symptoms, especially if the patient has a history of liver disease. A screen that includes a plasma ceruloplasmin level and an ophthalmology examination for K-F rings would be prudent.30
The renal dysfunction that results from copper accumulation in the kidneys includes proximal renal tubular dysfunction, and decreased glomerular filtration rate.31 The renal tubular dysfunctional is manifested by presence of blood, protein, glucose, phosphate, and amino acids in the urine and decreased ability to acidify the urine.19 Renal stones can be seen in up to 16% of Wilson’s patients. The patients with the most severe hepatic disease, that is, presentation with fulminant hepatic failure or end-stage liver disease, may develop renal insufficiency as well.
The primary hematologic manifestation of Wilson’s is intravascular hemolysis. The hemolysis may be caused by the oxidative stress resulting from sudden releases of copper from the liver. This damages red cell membranes via lipid peroxidation. Wilson’s patients may present with transient hemolysis in the absence of any hepatic or neuropsychiatric symptoms. Hemolysis is the presenting complaint in 15% of patients.32,33 If a patient presents with the combination of hemolysis and liver failure, the prognosis is poor because of possible associated renal failure secondary to hemoglobinuria.34,35
The hepatic disease of Wilson’s can present as one of the following four clinical subtypes: acute hepatitis, fulminant hepatic failure, chronic active hepatitis, and cirrhosis.36 However, it is also common to diagnose Wilson’s disease during investigation of elevated transaminases found on health screening in asymptomatic children. The presentation of acute hepatitis typically consists of jaundice, nausea, fatigue, dark urine, and pale stools. These patients will typically be tested for common infectious conditions such as hepatitis A, B, and C and Epstein–Barr virus (Table 25–2). If these are negative and the patient spontaneously improves, no further workup may occur. However, other clues to the possibility of Wilson’s disease include the presence of low serum uric acid (due to renal losses), low serum alkaline phosphatase (mechanism unknown), or a hemolytic anemia.2
|Presentation||Asymptomatic Elevation of AST and ALT||Chronic Hepatitis||Fulminant Hepatic Failure|
|Common conditions||Drug toxicity||Infectious hepatitis (B, C)||Drugs and toxins|
|Medications for||• Acetaminophen|
|• Attention deficit disorder||• Isoniazid|
|• Seizures||• Valproate|
|• Psychiatric disease||• Propylthiouracil|
|Nonalcoholic steatohepatitis||Nonalcoholic steatohepatitis||Viral hepatitis non-A–G|
|• Infectious hepatitis B, C|
|Rare conditions||Wilson’s disease||Wilson’s disease||Wilson’s disease|
|Autoimmune hepatitis||Autoimmune hepatitis||Autoimmune hepatitis|
|Primary sclerosing cholangitis||Primary sclerosing cholangitis||Ischemia/hypoperfusion|
|Alpha 1 antitrypsin deficiency||Alpha 1 antitrypsin deficiency||Erythrophagocytic lymphohistiocytosis|
|Celiac disease||Cystic fibrosis||Budd–Chiari|
|Muscle disease||Rheumatologic disease:|
|• Systemic lupus erythmatosis|
|• Juvenile rheumatoid arthritis|