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Review
Wilson Disease MOUNIF EL-YOUSSEF, MD Wilson disease is a rare disorder of copper metabolism that results in accumulation of copper in the liver and subsequently in other organs, mainly the central nervous system and the kidneys. Advances in the diagnosis and treatment of Wilson disease are discussed, with the emphasis that this is a disease of children, adolescents, and young adults. The myriad manifestations of Wilson disease make its diagnosis dependent on a high index of suspicion, and determination of its genetic background is helping to elucidate the genotype-phenotype correlation and the diversity of presentations. Treatment of Wilson disease has pro-
gressed from chelation therapy using D-penicillamine and trientine to the more recent use of zinc and finally to the establishment of liver transplantation as an urgent but excellent modality for fulminant presentation. The evolution of Wilson disease from a uniformly fatal disease to an eminently treatable disease during the past century is an example of the remarkable advances of modern medicine. Mayo Clin Proc. 2003;78:1126-1136 ATP = adenosine triphosphate; ATPase = adenosine triphosphatase; WD = Wilson disease
S
in as yet asymptomatic patients and established an objective method for confirming the clinical impression of the disease. The genetic basis for WD is linked to one of the transport proteins. The genetic abnormality was linked to the long arm of chromosome 13 by identifying the association of WD with esterase D deficiency in an inbred Arab family.7 Subsequent analysis revealed a defect in a P-type adenosine triphosphatase (ATPase) involved in the transport of copper across the trans-Golgi and into transport vesicles.8 Since then, more than 100 mutations of the ATP7B (adenosine triphosphate) gene have been identified, which has allowed work on genotype-phenotype correlation and prenatal screening.9,10
amuel Alexander Kinnier Wilson, an American-born neurologist working in Great Britain, first described progressive lenticular degeneration in 1912.1 He described 4 cases of a rare, familial, progressive, and invariably fatal disease involving young patients, manifested by involuntary movements, spasticity, dysphagia, dysarthria, and psychiatric symptoms. The disorder is characterized by bilateral softening of the lenticular nucleus and by cirrhosis of the liver. Wilson remarked that the disease is likely to be due to “a toxin associated with the hepatic cirrhosis and generated in connexion therewith.” In 1860, Frerichs described the first patient with Wilson disease (WD): a child with clinical and pathological features2 identical to those described by Wilson. Rumpel first identified the relationship between excess copper and the liver in 1913.3 In 1929, Vogt3 and then Haurowitz and Glazebrook3 reported on the excess of copper in the brain and liver of patients dying of WD. The excess copper in the cornea, or Kayser-Fleischer ring, was demonstrated by Policard et al in 1936.3-5 In 1956, Bennetts and Chapman6 established the relationship between copper metabolism abnormalities and WD after demonstrating excessive urinary copper excretion. In 1952, Sternlieb and Gitlin found an almost universal low level of ceruloplasmin in the sera from patients with WD.6 This finding allowed the diagnosis of WD to be made
COPPER METABOLISM AND PATHOPHYSIOLOGY OF WD Copper is an essential metal for the function of a variety of enzymes.3 Trace amounts of copper are required for enzymatic reactions involving connective tissue (lysyl oxidase), free radical scavenging (superoxide dismutase), electron transfer (cytochrome-c oxidase), pigment production (tyrosinase), and neurotransmission (monamine oxidase). Copper is also involved in connective tissue formation (lysyl oxidase) and iron homeostasis.2,3,11 Foods rich in copper include chocolate, nuts, and shellfish. The average daily intake of copper from the gastrointestinal tract is 1.5 to 5 mg, with most copper absorbed in the stomach and the duodenum. Excess copper intake induces the production of a metallothionein in the enterocyte that captures copper. This allows, through normal shedding of senescent cells, safe disposal of excess copper.11
From the Division of Gastroenterology and Hepatology and Internal Medicine and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minn. Individual reprints of this article are not available. Address correspondence to Mounif El-Youssef, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2003;78:1126-1136
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© 2003 Mayo Foundation for Medical Education and Research
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Figure 1. Pathway of copper metabolism. The bar represents the metabolic abnormality of Wilson disease. In the absence of normal ATP7B, intracellular trafficking of copper is inadequate, resulting in copper accumulation and increased degradation of the apoceruloplasmin form of the protein and subsequent low serum level. Excess copper eventually saturates the liver and other organs.
Copper is taken up by albumin, and the liver has a high affinity for copper-bound albumin. More than 90% of the copper bound to albumin is present in the liver within a short period after absorption. In the hepatocytes, copper is bound to a thiol-rich cytosolic protein and to specific copper enzymes. Copper is also incorporated into apo-ceruloplasmin, which has the ability to bind copper atoms. Holoceruloplasmin is a ceruloplasmin protein with a full complement of copper bound to the metal-binding motifs.12 The incorporation of copper into apo-ceruloplasmin depends on the action of a P-type ATPase that is located in the trans-Golgi and termed ATP7B. The protein has 6 metalbinding motifs in its N-terminal domain. This protein directs the incorporation of copper into both apo-ceruloplasmin and the lysosomes. The copper-rich ceruloplasmin is then released into the circulation with about 10% of the body’s copper bound to it.13,14 The only physiologic route of copper egress is through biliary secretion. Mutations in
this protein product are presumed to result in abnormal accumulation of copper in the liver and an inability of the cell to direct and mobilize the metal. The low ceruloplasmin level is presumed to be due to rapid intracellular and extracellular degradation of apo-ceruloplasmin (Figures 1 and 2). The ATP7B protein is expressed in the trans-Golgi network. It transports copper into the secretory pathway for subsequent incorporation into ceruloplasmin and into a vesicular compartment near the canalicular membrane. The copper in the vesicular compartment is excreted into bile, and the ATP7B is redistributed back to the Golgi. The mechanism of copper incorporation into the ATP7B ATPase depends on the function of cuproproteins that act as chaperone proteins for trafficking of intracellular copper. The mutations in ATP7B result in abnormal interaction between the ATPase and the chaperone proteins and in accumulation of copper in the cytoplasm (Figure 2).15,16
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Figure 2. Schematic representation of the transport mechanism of copper in the hepatocyte. The metal is transported into the canalicular membrane with the help of the ATP7B molecule from the trans-Golgi. Copper in the cytosol is incorporated into apo-ceruloplasmin for transportation to various enzymes and for plasma secretion. In the absence of normal transport, the copper is not excreted into bile, and ceruloplasmin is rapidly metabolized, leading to low serum levels and copper toxicosis.
Ceruloplasmin is a multicopper oxidase involved in the oxidation of selected substrates. The synthesis of holoceruloplasmin occurs in the hepatocyte, and the half-life of the protein is estimated to be 5 days. Ceruloplasmin is an acute phase reactant, and its level increases with inflammation, infection, and trauma. About 10% of the synthesized ceruloplasmin is secreted from the liver without copper and is degraded rapidly with a half-life of about 5 hours.17 The ceruloplasmin level is low in patients with WD and in heterozygous patients with aceruloplasminemia. In this latter category, there is no associated abnormal copperrelated liver pathology. However, the hepatocytes have a marked increase in iron content. The ceruloplasmin level is also low in newborns, infants during the first 6 months of life, patients with protein-losing enteropathy, and patients with liver cirrhosis of other causes.18,19 CLINICAL ASPECTS The original description by Wilson emphasized the neurologic aspects of WD. Since then, it has become clear that the neurologic manifestations occur in late stages and reflect the accumulation of copper after the liver has been saturated. Neurologic manifestations of the disease invariably follow liver involvement, even in silent and unrecognized disease.
Of importance, the diagnosis of WD should be considered in patients who have minimal, if any, evidence of the disorder and who present with subtle and nonspecific manifestations. A high index of suspicion for WD should be considered in the following, especially in adolescents and adults younger than 40 years: (1) patients with elevated liver enzymes found incidentally or in the context of an acute hepatitis episode; (2) patients with dysphagia and dysarthria not explained by other neurologic disorders; (3) patients with tremors and movement disorders; (4) patients with psychiatric symptoms and liver disease; (5) adolescents with mood disorders and minor elevations of liver test results; (6) patients with Coombs-negative hemolytic anemia; (7) patients with liver cirrhosis; and (8) patients with fulminant hepatic failure. Liver disease is the most frequent initial manifestation of WD. Overall, it accounts for almost 40% of newly diagnosed cases of WD. Neurologic manifestations are the second most likely presenting feature. At presentation, a quarter of patients with WD have involvement of more than 1 organ system. Hepatic Liver manifestations of WD range from asymptomatic elevation of enzymes to fulminant hepatic failure. In fact,
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90 Hepatic
80
Neurologic 70
Cases (%)
60 50 40 30 20 10 0
<10 y
10-18 y
>18 y
Figure 3. Distribution of hepatic and neurologic manifestations of Wilson disease by age. Note that hepatic manifestations predominate in the pediatric age group in contrast to the neurologic manifestations in individuals older than 18 years.
to be due to accumulation of large quantities of copper in the lysosomes with subsequent degranulation of proteolytic enzymes and then cell death.30 Fulminant hepatic failure due to WD has an almost 100% mortality rate unless liver transplantation is performed. Therefore, the clinician must consider WD in the differential diagnosis of any patient with liver failure and promptly suggest transplantation. Hemolysis is due to disruption of the red blood cell membrane and depletion of glutathione stores. In animal models, it appears that the serum level of copper causes hemolysis when it reaches 75 µg/dL.30 Chronic Hepatitis.—Wilson disease can present with features similar to other causes of active hepatitis, such as chronic viral hepatitis, chronic autoimmune hepatitis, or
35 30 25
Cases (%)
WD can mimic a variety of liver conditions, including autoimmune hepatitis, steatosis with or without hepatitis, cirrhosis, and fulminant hepatic failure.19,20 A substantial proportion of patients present between 3 and 18 years of age, and therefore WD manifests in the pediatric age group (Figure 3).21 A recent report of a 3-year-old child with acute hepatitis shows that WD can present in the preschool years.21 Therefore, any child older than 3 years with manifestations of liver disease should be screened for WD. Also, WD is diagnosed by screening when an affected family member is identified. Manifestations of WD in the liver occur at a younger age than in other organ systems. As shown in Figure 3, hepatic disease occurs in children and young adolescents in contrast to neurologic manifestations that occur in adults. This represents a general trend of clinical manifestations that may be related to variations of disease severity depending on genetic mutations. The presenting features of WD include the following18-22: (1) asymptomatic elevated liver enzymes found on routine blood testing, which can be a minor elevation of 1 to 2 times the upper limit of normal18; (2) bleeding diathesis with subsequent demonstration of end-stage liver disease due to cirrhosis, including initial esophageal variceal bleeding; (3) portal hypertension with hypersplenism as the major presentation; (4) chronic hepatitis with jaundice and malaise23; (5) acute hepatitis characterized by sudden onset of jaundice, hemolysis, anorexia, and fatigue, episode of which lasts 1 to 2 weeks and is often considered of viral etiology24; and (6) fulminant presentation (Figure 4) with severe coagulopathy and encephalopathy.24 Fulminant Hepatic Failure and Hemolysis.—Fulminant hepatic failure can be the presenting feature of WD.25,26 Often, the diagnosis is not entertained until the presumed viral hepatitis etiology is excluded.27,28 This serious complication can occur suddenly. Features that allow differentiation of fulminant failure due to WD from other causes include a high bilirubin level that is out of proportion to the modest elevations of the transaminases,29 evidence of hemolysis, normal or low alkaline phosphatase level, aspartate aminotransferase-alanine aminotransferase ratio greater than 4, and high serum copper level.22 Fulminant failure is often associated with renal toxicity due to excessive copper egress from dying hepatocytes and is associated with tubular dysfunction characterized by glycosuria, hypophosphatemia, and low uric acid. Of note, fulminant hepatitis with hemolysis occurs more frequently in female than in male patients. Intravascular hemolysis is an important component of fulminant WD and is due to the massive release of copper from dying hepatocytes. The exact mechanism that leads to massive necrosis of the liver is unknown, but it is presumed
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20 15 10 5 0
Acute hepatitis
Chronic hepatitis
Cirrhosis
Fulminant
Figure 4. Distribution of hepatic presentations of Wilson disease.
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tis causes of fulminant failure. Finally, liver histology may show pronounced fibrosis and/or cirrhosis (Figure 7) by the time the patient seeks medical attention.
Figure 5. Features typical of chronic hepatitis with portal inflammation by lymphocytic infiltration and piecemeal necrosis spilling into the parenchyma beyond the limiting plate. There is evidence of lobular disarray with hepatocyte cords that seem to be disrupted.
drug-related hepatitis. The characteristic feature that helps distinguish WD from other forms of chronic hepatitis is mild elevation of the liver enzymes compared to the severity of the pathological findings (Figure 5).21,23 Another important feature is the association with renal tubular dysfunction characterized by low phosphorus and uric acid levels. Chronic hepatitis with fibrosis and even cirrhosis can present with an acute hepatitis episode that leads to the discovery of chronic liver injury. Tables 1 and 2 summarize the clinical findings of WD from several published series.3,6 Because of variations in reporting, not all findings were described uniformly, hence the differences in the total number of cases. Pathology.—Pathological features of liver involvement in WD can be variable. On liver histology, there is no 1 feature pathognomonic for the diagnosis of WD. Even a rhodamine stain for copper is not sufficient for determining the diagnosis of WD on histological grounds alone. Liver histological findings can be indistinguishable from autoimmune hepatitis, with periportal inflammation, piecemeal necrosis, and lobular disarray (Figure 5). These features can be seen in autoimmune and drug-related hepatitis. Another feature is steatohepatitis, with inflammation and macrovesicular as well as microvesicular steatosis (Figure 6). The accumulation of fat is presumed to be due to oxidative injury to the mitochondria with subsequent alteration of lipid metabolism. The hepatitis is presumed to be due to lipid peroxidation, generation of reactive species, and depletion of glutathione. Again, microvesicular steatosis can be seen in hepatitis C and other metabolic liver disease in children. In fulminant hepatitis, massive hepatocyte loss is the hallmark of liver injury. The differential diagnosis must be made with viral and drug-related hepati-
Neurologic Neurologic manifestations of WD tend to be 1 of 2 presentations.31 The original description by Wilson emphasized the lenticular degenerative aspects of the disease, which tend to occur at a younger age.1 The pseudosclerosis type of presentation is more common in adulthood. Lenticular degeneration is associated with dystonia and is thought to be less responsive to chelation therapy, whereas the dysarthria and tremors associated with the later onset of pseudosclerosis tend to be more amenable to therapy. The frequency of neurologic presentations is outlined in Figure 3. Of note is the frequency of combined dysphagia and dysarthria to warrant prompt evaluation for copper toxicosis in any patient who presents with both dysarthria and an abnormal oral phase of the swallowing mechanism.32 Patients with WD may have an exclusive psychiatric presentation. In up to 20% of patients, psychiatric symptoms dominate31-33 and may include depression, phobias, compulsive and antisocial behaviors, or schizophrenic personality disorder. In children, the neurologic manifestations of the disease are rare before age 10 years, with dystonia being the most common feature.34,35 Dysarthria, tremors, dysphagia, and psychiatric disturbances occur in the second decade of life. Insidious dementia manifesting as antisocial behavior, impulsivity, and decreased intellectual performance can be detected with psychometric testing.33 In 1987, Saito26 described 283 cases of WD, showing that jaundice was the most frequent presenting symptom. In order of decreasing frequency, neurologic manifestations were tremors, dysarthria, clumsiness, drooling, and gait disturbance. Computed tomographic findings are more often abnormal in symptomatic than in asymptomatic patients. Computed tomography shows ventricular dilatation and hypodense areas from loss of tissue due to copper toxicity. The affected areas are viable and may show cortical, brainstem, basal ganglia, and posterior fossa hypodensity and atrophy. Positron emission tomography and magnetic resonance imaging may reveal more specific signal abnormalities. Ocular Yellow-brown discoloration of the Descemet membrane in the limbic area of the cornea is termed KayserFleischer ring.2,4 Kayser-Fleischer ring occurs in 98% of patients with neurologic disease and in 80% of all cases of WD. Accumulation of copper in this area can be demonstrated best by slit lamp examination but can be visible to
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Table 1. Spectrum of Clinical Manifestations of Wilson Disease Hepatic Acute liver failure Chronic hepatitis Steatosis Cholestasis Cirrhosis Cholelithiasis Ascites Portal hypertension Neurologic Ataxia Dysarthria Rigidity Seizures Spasticity Tremors Hematologic Hemolytic anemia Coagulopathy Thrombocytopenia Ocular Kayser-Fleischer rings Sunflower cataracts Renal Fanconi syndrome Acidification defect Lithiasis Psychiatric Dementia Depression Schizophrenia Skeletal Spasticity Joint pain
the naked eye. Kayser-Fleischer rings are not pathognomonic for WD and can be seen in other cases of cholestatic liver disease, such as primary biliary cirrhosis, autoimmune hepatitis, and intrahepatic cholestasis associated with prolonged parenteral nutrition. Sunflower cataracts are greenish gray and are seen on ophthalmoscopic examination of the anterior lens. They usually resolve with chelation therapy. Hematologic Hepatobiliary bilirubinate stones can be the result of hemolysis. Hemolysis can be massive in the context of hepatic fulminant failure or as a manifestation of chronic hepatitis. Hemolysis can be chronic and can be isolated or in combination with portal hypertension and splenomegaly. The patient may present initially to a hematologist before liver disease is recognized.26,34 Cholelithiasis can develop secondary to chronic hemolysis.36 Renal Renal manifestations of WD involve the glomerulus and the tubules.2,3 Variable azotemia occurs in as many as 20% of patients. Reduction in the glomerular filtration rate
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Table 2. Summary of Distribution of Clinical Manifestations of Wilson Disease From Several Published Series Cases Manifestations Hepatic Jaundice Hepatomegaly Pain Splenomegaly Ascites Coagulopathy Neurologic Dysarthria Tremor Drooling Gait Movement disorder Rigidity Hematologic Anemia Hemolysis Renal
Total*
No. (%)
491 491 327 491 451 491
236 (48) 103 (21) 35 (11) 114 (23) 43 (10) 97 (20)
367 367 367 367 276 316
104 (28) 86 (23) 80 (22) 63 (17) 20 (7) 34 (11)
276 276 276
10 (4) 19 (7) 21 (8)
*Because of variations in reporting, not all findings were described uniformly, hence the difference in total number of cases.
has been reported to vary from 10% to 14%. It is unclear whether the change in the glomerular filtration rate is a primary result of copper toxicity or is due to the renal disease associated with cirrhosis or both. Tubular disease is more clearly related to copper excess as evidenced by usual improvement with chelation therapy.37 The spectrum of tubular dysfunction varies from increased uricosuria to Fanconi syndrome with aminoaciduria, tubular acidosis, and various electrolyte abnormalities. Electrolyte abnormalities can result in nephrocalcinosis. The loss of glucose in the urine can compound the hypoglycemia of liver failure. Other Cardiac.—Cardiomyopathy, congestive heart failure, and conduction abnormalities have been described and are presumably the result of excess copper.4 Electrocardiographic changes have shown left ventricular hypertrophy, premature ventricular contractions, atrial fibrillation, and sinoatrial block. Pathological examination has revealed ventricular fibrosis and dilated cardiomyopathy. Endocrine.—Hypoparathyroidism is a complication of WD, and deposition of copper is one possible explanation. Endocrine manifestations of cirrhosis are another cause of metabolic disturbances that are not necessarily directly related to copper toxicity. Amenorrhea and testicular atrophy appear to be due to copper toxicity and not necessarily to cirrhosis.2-4 Muscle.—Rhabdomyolysis has been described and may be attributed to the toxicity of copper to mitochondrial function.2,3
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Figure 6. Steatosis and steatohepatitis associated with the accumulation of fat in a patient with Wilson disease. It is presumed that mitochondrial injury causes disruption of fatty acid oxidation with resultant lipid accumulation inside the hepatocytes.
Bones and Joints.—Arthritis of the large joints is due to copper deposition in the synovium. Osteoporosis and osteochondritis dissecans may also occur. Vitamin D–resistant rickets can be the result of renal dysfunction.2 DIAGNOSIS The diagnosis of WD rests on a high index of suspicion. Patients with minor elevations of liver enzymes or with either liver or neurologic manifestations of WD should be screened by obtaining a serum ceruloplasmin level. Values of ceruloplasmin can vary among laboratories and are increased in pregnancy. Ceruloplasmin, being an acute phase reactant, can be elevated to the low end of normal in approximately 20% of patients with WD. Therefore, measurement of the ceruloplasmin level alone is inadequate as
Figure 7. Established cirrhosis in a patient with Wilson disease. Note the extensive fibrosis bridging from one portal area to the next.
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a definitive diagnostic test for WD. However, it is an adequate first test for both patients and family members of patients with WD.27,28 Twenty-four hour urinary copper excretion is almost invariably increased in patients with WD. However, copper accumulation in the urine can be excessive in other cholestatic disorders; therefore, unless the copper level is substantially elevated beyond 1600 µg, which is typical of untreated WD, it cannot be used as a definitive test for the diagnosis of WD.12 Measurement of hepatic copper is the best and most definitive available test for evaluating WD. Invariably, in patients with WD, the value of hepatic copper exceeds 250 µg/g of dry tissue. Occasionally, patients with advanced cirrhosis may have slightly lower values. Excessive copper in the liver can be associated with other cholestatic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and familial cholestatic syndrome. However, the value is usually substantially lower than 250 µg/g of dry tissue (Table 3).3,11,12 Serum copper levels vary according to the timing of the measurement with regard to the clinical aspect of the disease. When the patient has hemolysis with or without fulminant presentation, the serum copper level can be elevated substantially. In patients with asymptomatic presentation of WD or in those with cirrhosis, the serum copper level is usually less than 100 µg/dL.11,12,37,38 Kayser-Fleischer ring is present in 98% of patients with neurologic manifestations of WD but is present in only 50% of patients with liver disease manifestations.32 Magnetic resonance imaging of the brain may show atrophy of the basal ganglia, midbrain, and pons, as well as a change in the white matter. These changes, in the context of other neurologic or hepatic manifestations of liver disease, point strongly to the diagnosis but are not specific enough to be considered pathognomonic of WD. The available tests for diagnosing WD are listed in Table 3. Measurement of hepatic copper remains the most definitive and practical test at the present time. Mutation analysis is available in a few research laboratories in the United States and may be helpful in determining the correlation between genotype mutations and phenotypic expression.38 GENETICS An autosomal recessive disorder of copper metabolism, WD occurs in 1 in 30,000 individuals. It is equally distributed in all ethnic groups and occurs worldwide.2,9 In 1987, genetic evaluation of an Arab family identified several members with WD and a mutation in the red blood cell enzyme esterase D. This established the location of WD on chromosome 13. Subsequent multipoint linkage analysis identified the abnormal gene to 13q14-q21. Sev-
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eral groups later identified the WD gene independently, which consists of a transcript of 7.5 kb expressed primarily in liver, kidney, and placenta tissue. It is expressed in other tissues at lower levels. The mutations in the WD gene result in a frequency of 1 in 30,000 persons. The genetic mutation is estimated to occur in 1 in 90 persons.7,9 The gene code for a trans-Golgi P-type ATP transport protein has several metal-binding domains, an ATP-binding domain, a cation channel, a phosphorylation region, and a transduction domain (Figure 8).8 The protein helps channel copper to the canalicular membrane of the hepatocyte to facilitate biliary excretion of excess copper. Copper is also incorporated into apo-ceruloplasmin for transport to other sites.15 When apo-ceruloplasmin is not bound to copper, it is degraded intracellularly. To date, more than 100 mutations have been detected. Most are missense mutations. The most common mutation involves a histidine to glutamine mutation at position 1069. This mutation is responsible for about 40% of cases of WD. Whether the variability of the disease affects the phenotypic expression is subject to speculation. Some early reports suggest that some mutations are associated with early onset of WD.38 Mutations that result in missense reading seem to cause a slow, progressive hepatic and neurologic deterioration, whereas mutations that result in lack of protein product seem to cause early and possibly fulminant hepatic presentation.39 Variability of presentation occurring in the same family suggests that other factors are operative in disease manifestation.40 The histidine-glutamine mutation results in abnormal folding of the protein and its misdirection to the endoplasmic reticulum with subsequent rapid degradation. Therefore, mutations may result in defective production, defective folding, defective transport function, defective intracellular traffic, and defective chaperone protein interaction.15,30,41-44 Genetic testing can be performed in family members of an index case.41,42 The patient’s DNA is used as a reference to recognize the disease-carrying chromosome in other members of the family. Screening of such members by using haplotype analysis with closely linked markers allows precise carrier detection with a margin of error of 1% to 2%. The slow and tedious process of genetic testing renders it unsuitable for routine detection of ill patients. The more traditional methods of biochemical testing are suitable for identifying index cases and for screening family members. Genetic testing is available at a few research laboratories.45,46 The biochemical tests used to diagnose WD are shown in Table 3. Although the genetic basis of WD is now established, the presence of more than 100 mutations renders genetic testing rather cumbersome, especially in patients with ful-
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Table 3. Biochemical Tests for the Diagnosis of WD* Test
WD
Normal
Ceruloplasmin† (mg/dL) 24-h urinary copper‡ (µg) Hepatic copper (µg/g) Serum copper§ (µg/dL) Slit lamp Brain MRI/CT
<20 >100 >250 <100 Kayser-Fleischer rings⁄⁄ Atrophy, basal ganglia, midbrain pons white matter
35-55 <50 <50 About 100 Absent …
*CT = computed tomography; MRI = magnetic resonance imaging; WD = Wilson disease. †Values of ceruloplasmin vary among laboratories. Values are increased in pregnancy and as an acute phase reactant; they are low in newborns and in patients with aceruloplasminemia, protein-losing enteropathies, and end-stage liver disease. ‡>1600 µg in untreated patients. §Value increases to >200 µg/dL in patients with fulminant failure. ⁄⁄Present in 98% of patients with neurologic disease but in only 50% of patients with liver disease.
minant presentations. Elevated copper in the liver occurs in cholestatic liver diseases such as biliary cirrhosis and autoimmune hepatitis, but other features can help distinguish these conditions from WD. The measurement of ceruloplasmin by using immunoassays includes both holoceruloplasmin and apo-ceruloplasmin. During an acute illness, the ceruloplasmin level may be increased to levels that would be considered in the reference range. Thus, up to a third of patients with WD may have a normal ceruloplasmin value. Conditions associated with low ceruloplasmin levels have been mentioned previously. Cirrhosis due to other causes can result in a low ceruloplasmin value40; therefore, determination of copper in tissue may be the only way to confirm the diagnosis of WD. THERAPY AND OUTCOME The rarity of WD makes it difficult to conduct double-blind placebo-controlled studies of sufficient statistical power to compare one regimen with another. Because of the myriad presentations of WD, it is equally difficult to measure outcomes in all major areas of presentation: neurologic, hepatic, and presymptomatic.47 D-Penicillamine
Historically, recognition of the copper-depleting effect of D-penicillamine led to its adoption as the first choice of chelation in treating copper excess. For more than 3 decades, it has been clear that D-penicillamine is capable of reversing the hepatic, neurologic, and psychiatric manifestations of the disease in most patients. Therefore, D-penicillamine is considered the gold standard of therapy against which other treatments are measured. Asymptomatic patients can be treated effectively and indefinitely, provided
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6 Metal-binding domains
1101/11012 1069 NH2
ATP binding
1266/1270 Phosphorylation COOH
769 776 778 943
Channel
Pro-Cys-Pro motif
Figure 8. P-type adenosine triphosphatase (ATPase) is responsible for the binding and transport of copper. Note the 6 copper-binding domains, the adenosine triphosphate (ATP)–binding domain, the phosphorylation domain, and the channel domain.
they remain compliant. D-penicillamine is effective treatment for patients with severe liver insufficiency who are free of encephalopathy.48 Although D-penicillamine is a chelating agent, reports of fulminant failure occurring in patients who discontinue the medication abruptly cast doubt on the ability of the drug to “de-copper” the liver. The mechanism of D-penicillamine may be multifactorial and may involve induction of intestinal metallothionein and/or complex formation in the cell with excess copper.49-51 The therapeutic regimen of D-penicillamine is 1 to 2 g/d in 4 divided doses 30 minutes before meals, and rapid mobilization of copper and increased excretion in the urine are expected. Slow and progressive amelioration of liver enzyme levels follows; it may take up to 1 year for complete resolution of hepatitis. Likewise, histological improvement occurs with the inflammatory changes, although less so with the fibrosis and portal hypertension. Several complications have been reported with both short-term use and long-term use of D-penicillamine.52 Hypersensitivity reactions are common and manifest as rash, fever, and lymphadenopathy. The rash occurs shortly after the initiation of therapy. Management may require a reduction in the dose and use of antihistamine medications or even corticosteroids. If therapy is resumed, the dose is gradually
increased over 10 days with or without corticosteroid cover. Life-threatening leukopenia and thrombocytopenia are less common but require immediate cessation of therapy. Fragility of the skin, such as damage to collagen and elastic tissue, has also been reported with long-term use. Pyridoxine supplementation should be initiated because D-penicillamine has a weak antipyridoxine effect. Pyridoxine deficiency may manifest with an intercurrent infection or a growth spurt. A weekly dose of 50 mg of pyridoxine provides adequate prophylaxis. In a patient receiving D-penicillamine, the complete blood cell count and liver enzymes should be monitored frequently and urinalysis performed often. A syndrome of acute neurologic deterioration has been observed after initiation of therapy in as many as 20% of patients. If this occurs, the dosage should be reduced to 250 mg/d. Trientine Trientine is used as alternative therapy for patients intolerant of penicillamine. Some experts consider trientine the first choice of therapy because of its lower incidence of adverse effects. The exact mechanism of action is unknown. Interestingly, the serum copper level will increase during therapy with trientine, suggesting that the mecha-
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nism of action may differ from that of D-penicillamine. The usual dosage is 1 to 2 g/d in 3 divided doses. Sideroblastic anemia is the major adverse effect of therapy. Most of the few but serious adverse effects of penicillamine, including the lupuslike syndrome, nephritis, and arthritis, subside with trientine therapy.53,54 Zinc The principal mode of action of zinc is presumed to be the induction of metallothionein in the intestine and the liver, thereby sequestering it. Studies have been unable to address the issue of zinc monotherapy as an effective “decoppering” agent since most patients had received other chelating agents. One study suggests continued accumulation of hepatic copper despite zinc therapy. Zinc therapy is efficacious in presymptomatic patients, but more data are needed to address its long-term efficacy.55 Zinc can be used in conjunction with another chelating agent or alone in the rare patient who develops intolerance to both penicillamine and trientine.56-58 The daily regimen of zinc sulfate is 50 to 75 mg in 2 or 3 divided doses to be taken between meals. This regimen will effectively maintain a neutral or even a negative copper balance.55
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cells to repopulate and regenerate the liver, but also normalization of biliary excretion of copper.62 CONCLUSION Wilson disease has evolved from a uniformly fatal disease to an eminently treatable condition. Our understanding of the disease has progressed from the clinical description to the biochemical and histological aspects and finally to the genetic basis of copper metabolism. As always, each advance poses new questions and challenges in diagnosis and management. Wilson disease should be considered in the differential diagnosis of any patient with abnormal liver function test results, in patients with fulminant hepatic failure, and in patients with an associated constellation of neurologic, hematologic, and hepatic disease. Of importance, WD occurs in children and adolescents; therefore, WD should be considered in the differential diagnosis of a serious metabolic cause in a child with liver disease. Finally, recognition of WD in any patient should prompt evaluation of the family and genetic counseling. It is imperative to initiate and maintain treatment of the asymptomatic patient as soon as the diagnosis of WD is made.
REFERENCES
Thiomolybdates Tetrahydromolybdate is an investigational drug that has not been approved by the Food and Drug Administration. It is considered particularly suited for the treatment of neurologic manifestations of WD because it is not associated with exacerbation on initiation of treatment. It interferes with copper absorption and binds to plasma copper. Adverse effects include bone marrow suppression and copper deficiency.2 Liver Transplantation Liver transplantation is critical for the patient with fulminant hepatic failure. In this setting, the use of livingrelated donor transplants results in copper metabolism that is similar to that in patients who are heterozygous genetic carriers because a parent is often the donor. Liver transplantation is also recommended for patients with cirrhosis who have end-stage liver disease. It is generally not recommended for patients with neurologic disease without pronounced liver deterioration. Hepatic manifestations are reversed by liver transplantation. Neurologic manifestations of the disease can be reversed by transplantation, but the number of cases is anecdotal.59-61 Recently, hepatocyte transplantation was performed in Long-Evans Cinnamon rats that model WD perfectly. The results were encouraging, showing not only normalization of histology, an indicator of the potential of transplanted
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13.
14.
Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912; 34:295-509. Loudianos G, Gitlin JD. Wilson’s disease. Semin Liver Dis. 2000; 20:353-364. Gitlin N. Wilson’s disease: the scourge of copper. J Hepatol. 1998;28:734-739. Kayser B. Ueber einen Fall fon angeborener grünlicher Verfärbung der Kornea. Klin Monatsbl Augenheilkd. 1902;40:22-25. Stremmel W, Meyerrose KW, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-726. Sternlieb I. Copper and the liver. Gastroenterology. 1980;78:16151628. Bowcock AM, Farrer LA, Cavalli-Sforza LL, et al. Mapping the Wilson disease locus to a cluster of linked polymorphic markers on chromosome 13. Am J Hum Genet. 1987;41:27-35. Adachi Y, Okuyama Y, Miya H, Kamisako T. Presence of ATPdependent copper transport in the hepatocyte canalicular membrane of the Long-Evans cinnamon rat, an animal model of Wilson disease. J Hepatol. 1997;26:216-217. Riordan SM, Williams R. The Wilson’s disease gene and phenotypic diversity. J Hepatol. 2001;34:165-171. Loudianos G, Dessi V, Lovicu M, et al. Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. J Med Genet. 1999;36:833-836. Gollan JL, Gollan TJ. Wilson disease in 1998: genetic, diagnostic and therapeutic aspects. J Hepatol. 1998;28(suppl 1):28-36. Pfeil SA, Lynn DJ. Wilson’s disease: copper unfettered. J Clin Gastroenterol. 1999;29:22-31. Hung IH, Suzuki M, Yamaguchi Y, Yuan DS, Klausner RD, Gitlin JD. Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. J Biol Chem. 1997;272:21461-21466. Payne AS, Kelly EJ, Gitlin JD. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci U S A. 1998;95:10854-10859.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
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15.
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
28.
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
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Schaefer M, Hopkins RG, Failla ML, Gitlin JD. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver. Am J Physiol. 1999;276(3, pt 1):G639G646. Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A. 2001;98:6848-6852. Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271-276. Cauza E, Maier-Dobersberger T, Polli C, Kaserer K, Kramer L, Ferenci P. Screening for Wilson’s disease in patients with liver diseases by serum ceruloplasmin. J Hepatol. 1997;27:358-362. Walshe JM. Diagnosis and treatment of presymptomatic Wilson’s disease. Lancet. 1988;2:435-437. Scott J, Gollan JL, Samourian S, Sherlock S. Wilson’s disease, presenting as chronic active hepatitis. Gastroenterology. 1978;74: 645-651. Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr. 2000;137: 719-722. Nazer H, Ede RJ, Mowat AP, Williams R. Wilson’s disease: clinical presentation and use of prognostic index. Gut. 1986;27:13771381. Schilsky ML, Scheinberg IH, Sternlieb I. Prognosis of Wilsonian chronic active hepatitis. Gastroenterology. 1991;100:762-767. Ferlan-Marolt V, Stepec S. Fulminant Wilsonian hepatitis unmasked by disease progression: report of a case and review of the literature. Dig Dis Sci. 1999;44:1054-1058. Yuce A, Kocak N, Gurakan F, Ozen H. Wilson’s disease presented with fulminating hepatic failure in children [letter]. Dig Dis Sci. 2000;45:704. Saito T. Presenting symptoms and natural history of Wilson disease. Eur J Pediatr. 1987;146:261-265. Martins da Costa C, Baldwin D, Portmann B, Lolin Y, Mowat AP, Mieli-Vergani G. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson’s disease. Hepatology. 1992;15:609-615. Sallie R, Katsiyiannakis L, Baldwin D, et al. Failure of simple biochemical indexes to reliably differentiate fulminant Wilson’s disease from other causes of fulminant liver failure. Hepatology. 1992;16:1206-1211. Kenngott S, Bilzer M. Inverse correlation of serum bilirubin and alkaline phosphatase in fulminant Wilson’s disease. J Hepatol. 1998;29:683. Sokol RJ, Twedt D, McKim JM Jr, et al. Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology. 1994;107:1788-1798. Willeit J, Kiechl SG. Wilson’s disease with neurological impairment but no Kayser-Fleischer rings [letter]. Lancet. 1991;337: 1426. Gow PJ, Smallwood RA, Angus PW, Smith AL, Wall AJ, Sewell RB. Diagnosis of Wilson’s disease: an experience over three decades. Gut. 2000;46:415-419. Topaloglu H, Gucuyener K, Orkun C, Renda Y. Tremor of tongue and dysarthria as the sole manifestation of Wilson’s disease. Clin Neurol Neurosurg. 1990;92:295-296. Walshe JM, Yealland M. Wilson’s disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry. 1992;55:692-696. Giacchino R, Marazzi MG, Barabino A, et al. Syndromic variability of Wilson’s disease in children: clinical study of 44 cases. Ital J Gastroenterol Hepatol. 1997;29:155-161. Rosenfield N, Grand RJ, Watkins JB, Ballantine TV, Levey RH. Cholelithiasis and Wilson disease. J Pediatr. 1978;92:210-213. Bearn AG, Yu TK, Gutman AB. Renal function in Wilson’s disease. J Clin Invest. 1957;36:1107-1114. Pyeritz RE. Genetic heterogeneity in Wilson disease: lessons from rare alleles [editorial]. Ann Intern Med. 1997;127:70-72. Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW. The Wilson disease gene: spectrum of mutations and their conse-
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40.
41. 42. 43.
44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.
55. 56. 57. 58. 59. 60. 61. 62.
quences [published correction appears in Nat Genet. 1995;9:451]. Nat Genet. 1995;9:210-217. Perman JA, Werlin SL, Grand RJ, Watkins JB. Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children. J Pediatr. 1979;94:564568. Petrukhin K, Fischer SG, Pirastu M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet. 1993;5:338-343. Houwen RH, Juyn J, Hoogenraad TU, Ploos van Amstel JK, Berger R. H714Q mutation in Wilson disease is associated with late, neurological presentation. J Med Genet. 1995;32:480-482. Kemppainen R, Palatsi R, Kallioinen M, Oikarinen A. A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. J Invest Dermatol. 1997;108:3539. Maier-Dobersberger T, Ferenci P, Polli C, et al. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction. Ann Intern Med. 1997;127:21-26. Gaffney D, Walker JL, O’Donnell JG, et al. DNA-based presymptomatic diagnosis of Wilson disease. J Inherit Metab Dis. 1992;15:161-170. Chowrimootoo GF, Andoh J, Seymour CA. Western blot analysis in patients with hypocaeruloplasminaemia. QJM. 1997;90:197202. Walshe JM. Treatment of Wilson’s disease: the historical background. QJM. 1996;89:553-555. Durand F, Bernuau J, Giostra E, et al. Wilson’s disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine. Gut. 2001;48:849-852. Walshe JM, Dixon AK. Dangers of non-compliance in Wilson’s disease. Lancet. 1986;1:845-847. Van Caillie-Bertrand M, Degenhart HJ, Luijendijk I, Bouquet J, Sinaasappel M. Wilson’s disease: assessment of D-penicillamine treatment. Arch Dis Child. 1985;60:652-655. Santos Silva EE, Sarles J, Buts JP, Sokal EM. Successful medical treatment of severely decompensated Wilson disease. J Pediatr. 1996;128:285-287. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore). 1992;71:139-164. Dubois RS, Rodgerson DO, Hambidge KM. Treatment of Wilson’s disease with triethylene tetramine hydrochloride (Trientine). J Pediatr Gastroenterol Nutr. 1990;10:77-81. Dahlman T, Hartvig P, Lofholm M, Nordlinder H, Loof L, Westermark K. Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). QJM. 1995;88: 609-616. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson’s disease with zinc XII: dose regimen requirements. Am J Med Sci. 1993;305:199-202. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P. Oral zinc therapy for Wilson’s disease. Ann Intern Med. 1983;99:314-319. Brewer GJ. Treatment of Wilson’s disease with zinc [letter]. J Lab Clin Med. 1999;134:322-324. Hoogenraad TU. Zinc treatment of Wilson’s disease [editorial]. J Lab Clin Med. 1998;132:240-241. Sternlieb I. Wilson’s disease: indications for liver transplants. Hepatology. 1984;4(1, suppl):15S-17S. Zitelli BJ, Malatack JJ, Gartner JC, et al. Orthotopic liver-transplantation in children with hepatic-based metabolic disease. Trans Proc. 1983;15:1284-1287. Bellary S, Hassanein T, Van Thiel DH. Liver transplantation for Wilson’s disease. J Hepatol. 1995;23:373-381. Irani AN, Malhi H, Slehria S, et al. Correction of liver disease following transplantation of normal rat hepatocytes into LongEvans Cinnamon rats modeling Wilson’s disease. Mol Ther. 2001; 3:302-309.
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Review
Wilson Disease MOUNIF EL-YOUSSEF, MD Wilson disease is a rare disorder of copper metabolism that results in accumulation of copper in the liver and subsequently in other organs, mainly the central nervous system and the kidneys. Advances in the diagnosis and treatment of Wilson disease are discussed, with the emphasis that this is a disease of children, adolescents, and young adults. The myriad manifestations of Wilson disease make its diagnosis dependent on a high index of suspicion, and determination of its genetic background is helping to elucidate the genotype-phenotype correlation and the diversity of presentations. Treatment of Wilson disease has pro-
gressed from chelation therapy using D-penicillamine and trientine to the more recent use of zinc and finally to the establishment of liver transplantation as an urgent but excellent modality for fulminant presentation. The evolution of Wilson disease from a uniformly fatal disease to an eminently treatable disease during the past century is an example of the remarkable advances of modern medicine. Mayo Clin Proc. 2003;78:1126-1136 ATP = adenosine triphosphate; ATPase = adenosine triphosphatase; WD = Wilson disease
S
in as yet asymptomatic patients and established an objective method for confirming the clinical impression of the disease. The genetic basis for WD is linked to one of the transport proteins. The genetic abnormality was linked to the long arm of chromosome 13 by identifying the association of WD with esterase D deficiency in an inbred Arab family.7 Subsequent analysis revealed a defect in a P-type adenosine triphosphatase (ATPase) involved in the transport of copper across the trans-Golgi and into transport vesicles.8 Since then, more than 100 mutations of the ATP7B (adenosine triphosphate) gene have been identified, which has allowed work on genotype-phenotype correlation and prenatal screening.9,10
amuel Alexander Kinnier Wilson, an American-born neurologist working in Great Britain, first described progressive lenticular degeneration in 1912.1 He described 4 cases of a rare, familial, progressive, and invariably fatal disease involving young patients, manifested by involuntary movements, spasticity, dysphagia, dysarthria, and psychiatric symptoms. The disorder is characterized by bilateral softening of the lenticular nucleus and by cirrhosis of the liver. Wilson remarked that the disease is likely to be due to “a toxin associated with the hepatic cirrhosis and generated in connexion therewith.” In 1860, Frerichs described the first patient with Wilson disease (WD): a child with clinical and pathological features2 identical to those described by Wilson. Rumpel first identified the relationship between excess copper and the liver in 1913.3 In 1929, Vogt3 and then Haurowitz and Glazebrook3 reported on the excess of copper in the brain and liver of patients dying of WD. The excess copper in the cornea, or Kayser-Fleischer ring, was demonstrated by Policard et al in 1936.3-5 In 1956, Bennetts and Chapman6 established the relationship between copper metabolism abnormalities and WD after demonstrating excessive urinary copper excretion. In 1952, Sternlieb and Gitlin found an almost universal low level of ceruloplasmin in the sera from patients with WD.6 This finding allowed the diagnosis of WD to be made
COPPER METABOLISM AND PATHOPHYSIOLOGY OF WD Copper is an essential metal for the function of a variety of enzymes.3 Trace amounts of copper are required for enzymatic reactions involving connective tissue (lysyl oxidase), free radical scavenging (superoxide dismutase), electron transfer (cytochrome-c oxidase), pigment production (tyrosinase), and neurotransmission (monamine oxidase). Copper is also involved in connective tissue formation (lysyl oxidase) and iron homeostasis.2,3,11 Foods rich in copper include chocolate, nuts, and shellfish. The average daily intake of copper from the gastrointestinal tract is 1.5 to 5 mg, with most copper absorbed in the stomach and the duodenum. Excess copper intake induces the production of a metallothionein in the enterocyte that captures copper. This allows, through normal shedding of senescent cells, safe disposal of excess copper.11
From the Division of Gastroenterology and Hepatology and Internal Medicine and Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minn. Individual reprints of this article are not available. Address correspondence to Mounif El-Youssef, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (e-mail: [email protected]). Mayo Clin Proc. 2003;78:1126-1136
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© 2003 Mayo Foundation for Medical Education and Research
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Figure 1. Pathway of copper metabolism. The bar represents the metabolic abnormality of Wilson disease. In the absence of normal ATP7B, intracellular trafficking of copper is inadequate, resulting in copper accumulation and increased degradation of the apoceruloplasmin form of the protein and subsequent low serum level. Excess copper eventually saturates the liver and other organs.
Copper is taken up by albumin, and the liver has a high affinity for copper-bound albumin. More than 90% of the copper bound to albumin is present in the liver within a short period after absorption. In the hepatocytes, copper is bound to a thiol-rich cytosolic protein and to specific copper enzymes. Copper is also incorporated into apo-ceruloplasmin, which has the ability to bind copper atoms. Holoceruloplasmin is a ceruloplasmin protein with a full complement of copper bound to the metal-binding motifs.12 The incorporation of copper into apo-ceruloplasmin depends on the action of a P-type ATPase that is located in the trans-Golgi and termed ATP7B. The protein has 6 metalbinding motifs in its N-terminal domain. This protein directs the incorporation of copper into both apo-ceruloplasmin and the lysosomes. The copper-rich ceruloplasmin is then released into the circulation with about 10% of the body’s copper bound to it.13,14 The only physiologic route of copper egress is through biliary secretion. Mutations in
this protein product are presumed to result in abnormal accumulation of copper in the liver and an inability of the cell to direct and mobilize the metal. The low ceruloplasmin level is presumed to be due to rapid intracellular and extracellular degradation of apo-ceruloplasmin (Figures 1 and 2). The ATP7B protein is expressed in the trans-Golgi network. It transports copper into the secretory pathway for subsequent incorporation into ceruloplasmin and into a vesicular compartment near the canalicular membrane. The copper in the vesicular compartment is excreted into bile, and the ATP7B is redistributed back to the Golgi. The mechanism of copper incorporation into the ATP7B ATPase depends on the function of cuproproteins that act as chaperone proteins for trafficking of intracellular copper. The mutations in ATP7B result in abnormal interaction between the ATPase and the chaperone proteins and in accumulation of copper in the cytoplasm (Figure 2).15,16
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Figure 2. Schematic representation of the transport mechanism of copper in the hepatocyte. The metal is transported into the canalicular membrane with the help of the ATP7B molecule from the trans-Golgi. Copper in the cytosol is incorporated into apo-ceruloplasmin for transportation to various enzymes and for plasma secretion. In the absence of normal transport, the copper is not excreted into bile, and ceruloplasmin is rapidly metabolized, leading to low serum levels and copper toxicosis.
Ceruloplasmin is a multicopper oxidase involved in the oxidation of selected substrates. The synthesis of holoceruloplasmin occurs in the hepatocyte, and the half-life of the protein is estimated to be 5 days. Ceruloplasmin is an acute phase reactant, and its level increases with inflammation, infection, and trauma. About 10% of the synthesized ceruloplasmin is secreted from the liver without copper and is degraded rapidly with a half-life of about 5 hours.17 The ceruloplasmin level is low in patients with WD and in heterozygous patients with aceruloplasminemia. In this latter category, there is no associated abnormal copperrelated liver pathology. However, the hepatocytes have a marked increase in iron content. The ceruloplasmin level is also low in newborns, infants during the first 6 months of life, patients with protein-losing enteropathy, and patients with liver cirrhosis of other causes.18,19 CLINICAL ASPECTS The original description by Wilson emphasized the neurologic aspects of WD. Since then, it has become clear that the neurologic manifestations occur in late stages and reflect the accumulation of copper after the liver has been saturated. Neurologic manifestations of the disease invariably follow liver involvement, even in silent and unrecognized disease.
Of importance, the diagnosis of WD should be considered in patients who have minimal, if any, evidence of the disorder and who present with subtle and nonspecific manifestations. A high index of suspicion for WD should be considered in the following, especially in adolescents and adults younger than 40 years: (1) patients with elevated liver enzymes found incidentally or in the context of an acute hepatitis episode; (2) patients with dysphagia and dysarthria not explained by other neurologic disorders; (3) patients with tremors and movement disorders; (4) patients with psychiatric symptoms and liver disease; (5) adolescents with mood disorders and minor elevations of liver test results; (6) patients with Coombs-negative hemolytic anemia; (7) patients with liver cirrhosis; and (8) patients with fulminant hepatic failure. Liver disease is the most frequent initial manifestation of WD. Overall, it accounts for almost 40% of newly diagnosed cases of WD. Neurologic manifestations are the second most likely presenting feature. At presentation, a quarter of patients with WD have involvement of more than 1 organ system. Hepatic Liver manifestations of WD range from asymptomatic elevation of enzymes to fulminant hepatic failure. In fact,
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90 Hepatic
80
Neurologic 70
Cases (%)
60 50 40 30 20 10 0
<10 y
10-18 y
>18 y
Figure 3. Distribution of hepatic and neurologic manifestations of Wilson disease by age. Note that hepatic manifestations predominate in the pediatric age group in contrast to the neurologic manifestations in individuals older than 18 years.
to be due to accumulation of large quantities of copper in the lysosomes with subsequent degranulation of proteolytic enzymes and then cell death.30 Fulminant hepatic failure due to WD has an almost 100% mortality rate unless liver transplantation is performed. Therefore, the clinician must consider WD in the differential diagnosis of any patient with liver failure and promptly suggest transplantation. Hemolysis is due to disruption of the red blood cell membrane and depletion of glutathione stores. In animal models, it appears that the serum level of copper causes hemolysis when it reaches 75 µg/dL.30 Chronic Hepatitis.—Wilson disease can present with features similar to other causes of active hepatitis, such as chronic viral hepatitis, chronic autoimmune hepatitis, or
35 30 25
Cases (%)
WD can mimic a variety of liver conditions, including autoimmune hepatitis, steatosis with or without hepatitis, cirrhosis, and fulminant hepatic failure.19,20 A substantial proportion of patients present between 3 and 18 years of age, and therefore WD manifests in the pediatric age group (Figure 3).21 A recent report of a 3-year-old child with acute hepatitis shows that WD can present in the preschool years.21 Therefore, any child older than 3 years with manifestations of liver disease should be screened for WD. Also, WD is diagnosed by screening when an affected family member is identified. Manifestations of WD in the liver occur at a younger age than in other organ systems. As shown in Figure 3, hepatic disease occurs in children and young adolescents in contrast to neurologic manifestations that occur in adults. This represents a general trend of clinical manifestations that may be related to variations of disease severity depending on genetic mutations. The presenting features of WD include the following18-22: (1) asymptomatic elevated liver enzymes found on routine blood testing, which can be a minor elevation of 1 to 2 times the upper limit of normal18; (2) bleeding diathesis with subsequent demonstration of end-stage liver disease due to cirrhosis, including initial esophageal variceal bleeding; (3) portal hypertension with hypersplenism as the major presentation; (4) chronic hepatitis with jaundice and malaise23; (5) acute hepatitis characterized by sudden onset of jaundice, hemolysis, anorexia, and fatigue, episode of which lasts 1 to 2 weeks and is often considered of viral etiology24; and (6) fulminant presentation (Figure 4) with severe coagulopathy and encephalopathy.24 Fulminant Hepatic Failure and Hemolysis.—Fulminant hepatic failure can be the presenting feature of WD.25,26 Often, the diagnosis is not entertained until the presumed viral hepatitis etiology is excluded.27,28 This serious complication can occur suddenly. Features that allow differentiation of fulminant failure due to WD from other causes include a high bilirubin level that is out of proportion to the modest elevations of the transaminases,29 evidence of hemolysis, normal or low alkaline phosphatase level, aspartate aminotransferase-alanine aminotransferase ratio greater than 4, and high serum copper level.22 Fulminant failure is often associated with renal toxicity due to excessive copper egress from dying hepatocytes and is associated with tubular dysfunction characterized by glycosuria, hypophosphatemia, and low uric acid. Of note, fulminant hepatitis with hemolysis occurs more frequently in female than in male patients. Intravascular hemolysis is an important component of fulminant WD and is due to the massive release of copper from dying hepatocytes. The exact mechanism that leads to massive necrosis of the liver is unknown, but it is presumed
Wilson Disease
20 15 10 5 0
Acute hepatitis
Chronic hepatitis
Cirrhosis
Fulminant
Figure 4. Distribution of hepatic presentations of Wilson disease.
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tis causes of fulminant failure. Finally, liver histology may show pronounced fibrosis and/or cirrhosis (Figure 7) by the time the patient seeks medical attention.
Figure 5. Features typical of chronic hepatitis with portal inflammation by lymphocytic infiltration and piecemeal necrosis spilling into the parenchyma beyond the limiting plate. There is evidence of lobular disarray with hepatocyte cords that seem to be disrupted.
drug-related hepatitis. The characteristic feature that helps distinguish WD from other forms of chronic hepatitis is mild elevation of the liver enzymes compared to the severity of the pathological findings (Figure 5).21,23 Another important feature is the association with renal tubular dysfunction characterized by low phosphorus and uric acid levels. Chronic hepatitis with fibrosis and even cirrhosis can present with an acute hepatitis episode that leads to the discovery of chronic liver injury. Tables 1 and 2 summarize the clinical findings of WD from several published series.3,6 Because of variations in reporting, not all findings were described uniformly, hence the differences in the total number of cases. Pathology.—Pathological features of liver involvement in WD can be variable. On liver histology, there is no 1 feature pathognomonic for the diagnosis of WD. Even a rhodamine stain for copper is not sufficient for determining the diagnosis of WD on histological grounds alone. Liver histological findings can be indistinguishable from autoimmune hepatitis, with periportal inflammation, piecemeal necrosis, and lobular disarray (Figure 5). These features can be seen in autoimmune and drug-related hepatitis. Another feature is steatohepatitis, with inflammation and macrovesicular as well as microvesicular steatosis (Figure 6). The accumulation of fat is presumed to be due to oxidative injury to the mitochondria with subsequent alteration of lipid metabolism. The hepatitis is presumed to be due to lipid peroxidation, generation of reactive species, and depletion of glutathione. Again, microvesicular steatosis can be seen in hepatitis C and other metabolic liver disease in children. In fulminant hepatitis, massive hepatocyte loss is the hallmark of liver injury. The differential diagnosis must be made with viral and drug-related hepati-
Neurologic Neurologic manifestations of WD tend to be 1 of 2 presentations.31 The original description by Wilson emphasized the lenticular degenerative aspects of the disease, which tend to occur at a younger age.1 The pseudosclerosis type of presentation is more common in adulthood. Lenticular degeneration is associated with dystonia and is thought to be less responsive to chelation therapy, whereas the dysarthria and tremors associated with the later onset of pseudosclerosis tend to be more amenable to therapy. The frequency of neurologic presentations is outlined in Figure 3. Of note is the frequency of combined dysphagia and dysarthria to warrant prompt evaluation for copper toxicosis in any patient who presents with both dysarthria and an abnormal oral phase of the swallowing mechanism.32 Patients with WD may have an exclusive psychiatric presentation. In up to 20% of patients, psychiatric symptoms dominate31-33 and may include depression, phobias, compulsive and antisocial behaviors, or schizophrenic personality disorder. In children, the neurologic manifestations of the disease are rare before age 10 years, with dystonia being the most common feature.34,35 Dysarthria, tremors, dysphagia, and psychiatric disturbances occur in the second decade of life. Insidious dementia manifesting as antisocial behavior, impulsivity, and decreased intellectual performance can be detected with psychometric testing.33 In 1987, Saito26 described 283 cases of WD, showing that jaundice was the most frequent presenting symptom. In order of decreasing frequency, neurologic manifestations were tremors, dysarthria, clumsiness, drooling, and gait disturbance. Computed tomographic findings are more often abnormal in symptomatic than in asymptomatic patients. Computed tomography shows ventricular dilatation and hypodense areas from loss of tissue due to copper toxicity. The affected areas are viable and may show cortical, brainstem, basal ganglia, and posterior fossa hypodensity and atrophy. Positron emission tomography and magnetic resonance imaging may reveal more specific signal abnormalities. Ocular Yellow-brown discoloration of the Descemet membrane in the limbic area of the cornea is termed KayserFleischer ring.2,4 Kayser-Fleischer ring occurs in 98% of patients with neurologic disease and in 80% of all cases of WD. Accumulation of copper in this area can be demonstrated best by slit lamp examination but can be visible to
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Table 1. Spectrum of Clinical Manifestations of Wilson Disease Hepatic Acute liver failure Chronic hepatitis Steatosis Cholestasis Cirrhosis Cholelithiasis Ascites Portal hypertension Neurologic Ataxia Dysarthria Rigidity Seizures Spasticity Tremors Hematologic Hemolytic anemia Coagulopathy Thrombocytopenia Ocular Kayser-Fleischer rings Sunflower cataracts Renal Fanconi syndrome Acidification defect Lithiasis Psychiatric Dementia Depression Schizophrenia Skeletal Spasticity Joint pain
the naked eye. Kayser-Fleischer rings are not pathognomonic for WD and can be seen in other cases of cholestatic liver disease, such as primary biliary cirrhosis, autoimmune hepatitis, and intrahepatic cholestasis associated with prolonged parenteral nutrition. Sunflower cataracts are greenish gray and are seen on ophthalmoscopic examination of the anterior lens. They usually resolve with chelation therapy. Hematologic Hepatobiliary bilirubinate stones can be the result of hemolysis. Hemolysis can be massive in the context of hepatic fulminant failure or as a manifestation of chronic hepatitis. Hemolysis can be chronic and can be isolated or in combination with portal hypertension and splenomegaly. The patient may present initially to a hematologist before liver disease is recognized.26,34 Cholelithiasis can develop secondary to chronic hemolysis.36 Renal Renal manifestations of WD involve the glomerulus and the tubules.2,3 Variable azotemia occurs in as many as 20% of patients. Reduction in the glomerular filtration rate
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Table 2. Summary of Distribution of Clinical Manifestations of Wilson Disease From Several Published Series Cases Manifestations Hepatic Jaundice Hepatomegaly Pain Splenomegaly Ascites Coagulopathy Neurologic Dysarthria Tremor Drooling Gait Movement disorder Rigidity Hematologic Anemia Hemolysis Renal
Total*
No. (%)
491 491 327 491 451 491
236 (48) 103 (21) 35 (11) 114 (23) 43 (10) 97 (20)
367 367 367 367 276 316
104 (28) 86 (23) 80 (22) 63 (17) 20 (7) 34 (11)
276 276 276
10 (4) 19 (7) 21 (8)
*Because of variations in reporting, not all findings were described uniformly, hence the difference in total number of cases.
has been reported to vary from 10% to 14%. It is unclear whether the change in the glomerular filtration rate is a primary result of copper toxicity or is due to the renal disease associated with cirrhosis or both. Tubular disease is more clearly related to copper excess as evidenced by usual improvement with chelation therapy.37 The spectrum of tubular dysfunction varies from increased uricosuria to Fanconi syndrome with aminoaciduria, tubular acidosis, and various electrolyte abnormalities. Electrolyte abnormalities can result in nephrocalcinosis. The loss of glucose in the urine can compound the hypoglycemia of liver failure. Other Cardiac.—Cardiomyopathy, congestive heart failure, and conduction abnormalities have been described and are presumably the result of excess copper.4 Electrocardiographic changes have shown left ventricular hypertrophy, premature ventricular contractions, atrial fibrillation, and sinoatrial block. Pathological examination has revealed ventricular fibrosis and dilated cardiomyopathy. Endocrine.—Hypoparathyroidism is a complication of WD, and deposition of copper is one possible explanation. Endocrine manifestations of cirrhosis are another cause of metabolic disturbances that are not necessarily directly related to copper toxicity. Amenorrhea and testicular atrophy appear to be due to copper toxicity and not necessarily to cirrhosis.2-4 Muscle.—Rhabdomyolysis has been described and may be attributed to the toxicity of copper to mitochondrial function.2,3
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Wilson Disease
Figure 6. Steatosis and steatohepatitis associated with the accumulation of fat in a patient with Wilson disease. It is presumed that mitochondrial injury causes disruption of fatty acid oxidation with resultant lipid accumulation inside the hepatocytes.
Bones and Joints.—Arthritis of the large joints is due to copper deposition in the synovium. Osteoporosis and osteochondritis dissecans may also occur. Vitamin D–resistant rickets can be the result of renal dysfunction.2 DIAGNOSIS The diagnosis of WD rests on a high index of suspicion. Patients with minor elevations of liver enzymes or with either liver or neurologic manifestations of WD should be screened by obtaining a serum ceruloplasmin level. Values of ceruloplasmin can vary among laboratories and are increased in pregnancy. Ceruloplasmin, being an acute phase reactant, can be elevated to the low end of normal in approximately 20% of patients with WD. Therefore, measurement of the ceruloplasmin level alone is inadequate as
Figure 7. Established cirrhosis in a patient with Wilson disease. Note the extensive fibrosis bridging from one portal area to the next.
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a definitive diagnostic test for WD. However, it is an adequate first test for both patients and family members of patients with WD.27,28 Twenty-four hour urinary copper excretion is almost invariably increased in patients with WD. However, copper accumulation in the urine can be excessive in other cholestatic disorders; therefore, unless the copper level is substantially elevated beyond 1600 µg, which is typical of untreated WD, it cannot be used as a definitive test for the diagnosis of WD.12 Measurement of hepatic copper is the best and most definitive available test for evaluating WD. Invariably, in patients with WD, the value of hepatic copper exceeds 250 µg/g of dry tissue. Occasionally, patients with advanced cirrhosis may have slightly lower values. Excessive copper in the liver can be associated with other cholestatic liver diseases, such as primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, and familial cholestatic syndrome. However, the value is usually substantially lower than 250 µg/g of dry tissue (Table 3).3,11,12 Serum copper levels vary according to the timing of the measurement with regard to the clinical aspect of the disease. When the patient has hemolysis with or without fulminant presentation, the serum copper level can be elevated substantially. In patients with asymptomatic presentation of WD or in those with cirrhosis, the serum copper level is usually less than 100 µg/dL.11,12,37,38 Kayser-Fleischer ring is present in 98% of patients with neurologic manifestations of WD but is present in only 50% of patients with liver disease manifestations.32 Magnetic resonance imaging of the brain may show atrophy of the basal ganglia, midbrain, and pons, as well as a change in the white matter. These changes, in the context of other neurologic or hepatic manifestations of liver disease, point strongly to the diagnosis but are not specific enough to be considered pathognomonic of WD. The available tests for diagnosing WD are listed in Table 3. Measurement of hepatic copper remains the most definitive and practical test at the present time. Mutation analysis is available in a few research laboratories in the United States and may be helpful in determining the correlation between genotype mutations and phenotypic expression.38 GENETICS An autosomal recessive disorder of copper metabolism, WD occurs in 1 in 30,000 individuals. It is equally distributed in all ethnic groups and occurs worldwide.2,9 In 1987, genetic evaluation of an Arab family identified several members with WD and a mutation in the red blood cell enzyme esterase D. This established the location of WD on chromosome 13. Subsequent multipoint linkage analysis identified the abnormal gene to 13q14-q21. Sev-
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Mayo Clin Proc, September 2003, Vol 78
eral groups later identified the WD gene independently, which consists of a transcript of 7.5 kb expressed primarily in liver, kidney, and placenta tissue. It is expressed in other tissues at lower levels. The mutations in the WD gene result in a frequency of 1 in 30,000 persons. The genetic mutation is estimated to occur in 1 in 90 persons.7,9 The gene code for a trans-Golgi P-type ATP transport protein has several metal-binding domains, an ATP-binding domain, a cation channel, a phosphorylation region, and a transduction domain (Figure 8).8 The protein helps channel copper to the canalicular membrane of the hepatocyte to facilitate biliary excretion of excess copper. Copper is also incorporated into apo-ceruloplasmin for transport to other sites.15 When apo-ceruloplasmin is not bound to copper, it is degraded intracellularly. To date, more than 100 mutations have been detected. Most are missense mutations. The most common mutation involves a histidine to glutamine mutation at position 1069. This mutation is responsible for about 40% of cases of WD. Whether the variability of the disease affects the phenotypic expression is subject to speculation. Some early reports suggest that some mutations are associated with early onset of WD.38 Mutations that result in missense reading seem to cause a slow, progressive hepatic and neurologic deterioration, whereas mutations that result in lack of protein product seem to cause early and possibly fulminant hepatic presentation.39 Variability of presentation occurring in the same family suggests that other factors are operative in disease manifestation.40 The histidine-glutamine mutation results in abnormal folding of the protein and its misdirection to the endoplasmic reticulum with subsequent rapid degradation. Therefore, mutations may result in defective production, defective folding, defective transport function, defective intracellular traffic, and defective chaperone protein interaction.15,30,41-44 Genetic testing can be performed in family members of an index case.41,42 The patient’s DNA is used as a reference to recognize the disease-carrying chromosome in other members of the family. Screening of such members by using haplotype analysis with closely linked markers allows precise carrier detection with a margin of error of 1% to 2%. The slow and tedious process of genetic testing renders it unsuitable for routine detection of ill patients. The more traditional methods of biochemical testing are suitable for identifying index cases and for screening family members. Genetic testing is available at a few research laboratories.45,46 The biochemical tests used to diagnose WD are shown in Table 3. Although the genetic basis of WD is now established, the presence of more than 100 mutations renders genetic testing rather cumbersome, especially in patients with ful-
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Table 3. Biochemical Tests for the Diagnosis of WD* Test
WD
Normal
Ceruloplasmin† (mg/dL) 24-h urinary copper‡ (µg) Hepatic copper (µg/g) Serum copper§ (µg/dL) Slit lamp Brain MRI/CT
<20 >100 >250 <100 Kayser-Fleischer rings⁄⁄ Atrophy, basal ganglia, midbrain pons white matter
35-55 <50 <50 About 100 Absent …
*CT = computed tomography; MRI = magnetic resonance imaging; WD = Wilson disease. †Values of ceruloplasmin vary among laboratories. Values are increased in pregnancy and as an acute phase reactant; they are low in newborns and in patients with aceruloplasminemia, protein-losing enteropathies, and end-stage liver disease. ‡>1600 µg in untreated patients. §Value increases to >200 µg/dL in patients with fulminant failure. ⁄⁄Present in 98% of patients with neurologic disease but in only 50% of patients with liver disease.
minant presentations. Elevated copper in the liver occurs in cholestatic liver diseases such as biliary cirrhosis and autoimmune hepatitis, but other features can help distinguish these conditions from WD. The measurement of ceruloplasmin by using immunoassays includes both holoceruloplasmin and apo-ceruloplasmin. During an acute illness, the ceruloplasmin level may be increased to levels that would be considered in the reference range. Thus, up to a third of patients with WD may have a normal ceruloplasmin value. Conditions associated with low ceruloplasmin levels have been mentioned previously. Cirrhosis due to other causes can result in a low ceruloplasmin value40; therefore, determination of copper in tissue may be the only way to confirm the diagnosis of WD. THERAPY AND OUTCOME The rarity of WD makes it difficult to conduct double-blind placebo-controlled studies of sufficient statistical power to compare one regimen with another. Because of the myriad presentations of WD, it is equally difficult to measure outcomes in all major areas of presentation: neurologic, hepatic, and presymptomatic.47 D-Penicillamine
Historically, recognition of the copper-depleting effect of D-penicillamine led to its adoption as the first choice of chelation in treating copper excess. For more than 3 decades, it has been clear that D-penicillamine is capable of reversing the hepatic, neurologic, and psychiatric manifestations of the disease in most patients. Therefore, D-penicillamine is considered the gold standard of therapy against which other treatments are measured. Asymptomatic patients can be treated effectively and indefinitely, provided
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6 Metal-binding domains
1101/11012 1069 NH2
ATP binding
1266/1270 Phosphorylation COOH
769 776 778 943
Channel
Pro-Cys-Pro motif
Figure 8. P-type adenosine triphosphatase (ATPase) is responsible for the binding and transport of copper. Note the 6 copper-binding domains, the adenosine triphosphate (ATP)–binding domain, the phosphorylation domain, and the channel domain.
they remain compliant. D-penicillamine is effective treatment for patients with severe liver insufficiency who are free of encephalopathy.48 Although D-penicillamine is a chelating agent, reports of fulminant failure occurring in patients who discontinue the medication abruptly cast doubt on the ability of the drug to “de-copper” the liver. The mechanism of D-penicillamine may be multifactorial and may involve induction of intestinal metallothionein and/or complex formation in the cell with excess copper.49-51 The therapeutic regimen of D-penicillamine is 1 to 2 g/d in 4 divided doses 30 minutes before meals, and rapid mobilization of copper and increased excretion in the urine are expected. Slow and progressive amelioration of liver enzyme levels follows; it may take up to 1 year for complete resolution of hepatitis. Likewise, histological improvement occurs with the inflammatory changes, although less so with the fibrosis and portal hypertension. Several complications have been reported with both short-term use and long-term use of D-penicillamine.52 Hypersensitivity reactions are common and manifest as rash, fever, and lymphadenopathy. The rash occurs shortly after the initiation of therapy. Management may require a reduction in the dose and use of antihistamine medications or even corticosteroids. If therapy is resumed, the dose is gradually
increased over 10 days with or without corticosteroid cover. Life-threatening leukopenia and thrombocytopenia are less common but require immediate cessation of therapy. Fragility of the skin, such as damage to collagen and elastic tissue, has also been reported with long-term use. Pyridoxine supplementation should be initiated because D-penicillamine has a weak antipyridoxine effect. Pyridoxine deficiency may manifest with an intercurrent infection or a growth spurt. A weekly dose of 50 mg of pyridoxine provides adequate prophylaxis. In a patient receiving D-penicillamine, the complete blood cell count and liver enzymes should be monitored frequently and urinalysis performed often. A syndrome of acute neurologic deterioration has been observed after initiation of therapy in as many as 20% of patients. If this occurs, the dosage should be reduced to 250 mg/d. Trientine Trientine is used as alternative therapy for patients intolerant of penicillamine. Some experts consider trientine the first choice of therapy because of its lower incidence of adverse effects. The exact mechanism of action is unknown. Interestingly, the serum copper level will increase during therapy with trientine, suggesting that the mecha-
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Mayo Clin Proc, September 2003, Vol 78
nism of action may differ from that of D-penicillamine. The usual dosage is 1 to 2 g/d in 3 divided doses. Sideroblastic anemia is the major adverse effect of therapy. Most of the few but serious adverse effects of penicillamine, including the lupuslike syndrome, nephritis, and arthritis, subside with trientine therapy.53,54 Zinc The principal mode of action of zinc is presumed to be the induction of metallothionein in the intestine and the liver, thereby sequestering it. Studies have been unable to address the issue of zinc monotherapy as an effective “decoppering” agent since most patients had received other chelating agents. One study suggests continued accumulation of hepatic copper despite zinc therapy. Zinc therapy is efficacious in presymptomatic patients, but more data are needed to address its long-term efficacy.55 Zinc can be used in conjunction with another chelating agent or alone in the rare patient who develops intolerance to both penicillamine and trientine.56-58 The daily regimen of zinc sulfate is 50 to 75 mg in 2 or 3 divided doses to be taken between meals. This regimen will effectively maintain a neutral or even a negative copper balance.55
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cells to repopulate and regenerate the liver, but also normalization of biliary excretion of copper.62 CONCLUSION Wilson disease has evolved from a uniformly fatal disease to an eminently treatable condition. Our understanding of the disease has progressed from the clinical description to the biochemical and histological aspects and finally to the genetic basis of copper metabolism. As always, each advance poses new questions and challenges in diagnosis and management. Wilson disease should be considered in the differential diagnosis of any patient with abnormal liver function test results, in patients with fulminant hepatic failure, and in patients with an associated constellation of neurologic, hematologic, and hepatic disease. Of importance, WD occurs in children and adolescents; therefore, WD should be considered in the differential diagnosis of a serious metabolic cause in a child with liver disease. Finally, recognition of WD in any patient should prompt evaluation of the family and genetic counseling. It is imperative to initiate and maintain treatment of the asymptomatic patient as soon as the diagnosis of WD is made.
REFERENCES
Thiomolybdates Tetrahydromolybdate is an investigational drug that has not been approved by the Food and Drug Administration. It is considered particularly suited for the treatment of neurologic manifestations of WD because it is not associated with exacerbation on initiation of treatment. It interferes with copper absorption and binds to plasma copper. Adverse effects include bone marrow suppression and copper deficiency.2 Liver Transplantation Liver transplantation is critical for the patient with fulminant hepatic failure. In this setting, the use of livingrelated donor transplants results in copper metabolism that is similar to that in patients who are heterozygous genetic carriers because a parent is often the donor. Liver transplantation is also recommended for patients with cirrhosis who have end-stage liver disease. It is generally not recommended for patients with neurologic disease without pronounced liver deterioration. Hepatic manifestations are reversed by liver transplantation. Neurologic manifestations of the disease can be reversed by transplantation, but the number of cases is anecdotal.59-61 Recently, hepatocyte transplantation was performed in Long-Evans Cinnamon rats that model WD perfectly. The results were encouraging, showing not only normalization of histology, an indicator of the potential of transplanted
1. 2. 3. 4. 5. 6. 7. 8.
9. 10. 11. 12. 13.
14.
Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain. 1912; 34:295-509. Loudianos G, Gitlin JD. Wilson’s disease. Semin Liver Dis. 2000; 20:353-364. Gitlin N. Wilson’s disease: the scourge of copper. J Hepatol. 1998;28:734-739. Kayser B. Ueber einen Fall fon angeborener grünlicher Verfärbung der Kornea. Klin Monatsbl Augenheilkd. 1902;40:22-25. Stremmel W, Meyerrose KW, Niederau C, Hefter H, Kreuzpaintner G, Strohmeyer G. Wilson disease: clinical presentation, treatment, and survival. Ann Intern Med. 1991;115:720-726. Sternlieb I. Copper and the liver. Gastroenterology. 1980;78:16151628. Bowcock AM, Farrer LA, Cavalli-Sforza LL, et al. Mapping the Wilson disease locus to a cluster of linked polymorphic markers on chromosome 13. Am J Hum Genet. 1987;41:27-35. Adachi Y, Okuyama Y, Miya H, Kamisako T. Presence of ATPdependent copper transport in the hepatocyte canalicular membrane of the Long-Evans cinnamon rat, an animal model of Wilson disease. J Hepatol. 1997;26:216-217. Riordan SM, Williams R. The Wilson’s disease gene and phenotypic diversity. J Hepatol. 2001;34:165-171. Loudianos G, Dessi V, Lovicu M, et al. Mutation analysis in patients of Mediterranean descent with Wilson disease: identification of 19 novel mutations. J Med Genet. 1999;36:833-836. Gollan JL, Gollan TJ. Wilson disease in 1998: genetic, diagnostic and therapeutic aspects. J Hepatol. 1998;28(suppl 1):28-36. Pfeil SA, Lynn DJ. Wilson’s disease: copper unfettered. J Clin Gastroenterol. 1999;29:22-31. Hung IH, Suzuki M, Yamaguchi Y, Yuan DS, Klausner RD, Gitlin JD. Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. J Biol Chem. 1997;272:21461-21466. Payne AS, Kelly EJ, Gitlin JD. Functional expression of the Wilson disease protein reveals mislocalization and impaired copper-dependent trafficking of the common H1069Q mutation. Proc Natl Acad Sci U S A. 1998;95:10854-10859.
For personal use. Mass reproduce only with permission from Mayo Clinic Proceedings.
1136
15.
16. 17. 18. 19. 20. 21. 22. 23. 24. 25. 26. 27.
28.
29. 30. 31. 32. 33. 34. 35. 36. 37. 38. 39.
Wilson Disease
Schaefer M, Hopkins RG, Failla ML, Gitlin JD. Hepatocyte-specific localization and copper-dependent trafficking of the Wilson’s disease protein in the liver. Am J Physiol. 1999;276(3, pt 1):G639G646. Hamza I, Faisst A, Prohaska J, Chen J, Gruss P, Gitlin JD. The metallochaperone Atox1 plays a critical role in perinatal copper homeostasis. Proc Natl Acad Sci U S A. 2001;98:6848-6852. Gitlin JD. Aceruloplasminemia. Pediatr Res. 1998;44:271-276. Cauza E, Maier-Dobersberger T, Polli C, Kaserer K, Kramer L, Ferenci P. Screening for Wilson’s disease in patients with liver diseases by serum ceruloplasmin. J Hepatol. 1997;27:358-362. Walshe JM. Diagnosis and treatment of presymptomatic Wilson’s disease. Lancet. 1988;2:435-437. Scott J, Gollan JL, Samourian S, Sherlock S. Wilson’s disease, presenting as chronic active hepatitis. Gastroenterology. 1978;74: 645-651. Wilson DC, Phillips MJ, Cox DW, Roberts EA. Severe hepatic Wilson’s disease in preschool-aged children. J Pediatr. 2000;137: 719-722. Nazer H, Ede RJ, Mowat AP, Williams R. Wilson’s disease: clinical presentation and use of prognostic index. Gut. 1986;27:13771381. Schilsky ML, Scheinberg IH, Sternlieb I. Prognosis of Wilsonian chronic active hepatitis. Gastroenterology. 1991;100:762-767. Ferlan-Marolt V, Stepec S. Fulminant Wilsonian hepatitis unmasked by disease progression: report of a case and review of the literature. Dig Dis Sci. 1999;44:1054-1058. Yuce A, Kocak N, Gurakan F, Ozen H. Wilson’s disease presented with fulminating hepatic failure in children [letter]. Dig Dis Sci. 2000;45:704. Saito T. Presenting symptoms and natural history of Wilson disease. Eur J Pediatr. 1987;146:261-265. Martins da Costa C, Baldwin D, Portmann B, Lolin Y, Mowat AP, Mieli-Vergani G. Value of urinary copper excretion after penicillamine challenge in the diagnosis of Wilson’s disease. Hepatology. 1992;15:609-615. Sallie R, Katsiyiannakis L, Baldwin D, et al. Failure of simple biochemical indexes to reliably differentiate fulminant Wilson’s disease from other causes of fulminant liver failure. Hepatology. 1992;16:1206-1211. Kenngott S, Bilzer M. Inverse correlation of serum bilirubin and alkaline phosphatase in fulminant Wilson’s disease. J Hepatol. 1998;29:683. Sokol RJ, Twedt D, McKim JM Jr, et al. Oxidant injury to hepatic mitochondria in patients with Wilson’s disease and Bedlington terriers with copper toxicosis. Gastroenterology. 1994;107:1788-1798. Willeit J, Kiechl SG. Wilson’s disease with neurological impairment but no Kayser-Fleischer rings [letter]. Lancet. 1991;337: 1426. Gow PJ, Smallwood RA, Angus PW, Smith AL, Wall AJ, Sewell RB. Diagnosis of Wilson’s disease: an experience over three decades. Gut. 2000;46:415-419. Topaloglu H, Gucuyener K, Orkun C, Renda Y. Tremor of tongue and dysarthria as the sole manifestation of Wilson’s disease. Clin Neurol Neurosurg. 1990;92:295-296. Walshe JM, Yealland M. Wilson’s disease: the problem of delayed diagnosis. J Neurol Neurosurg Psychiatry. 1992;55:692-696. Giacchino R, Marazzi MG, Barabino A, et al. Syndromic variability of Wilson’s disease in children: clinical study of 44 cases. Ital J Gastroenterol Hepatol. 1997;29:155-161. Rosenfield N, Grand RJ, Watkins JB, Ballantine TV, Levey RH. Cholelithiasis and Wilson disease. J Pediatr. 1978;92:210-213. Bearn AG, Yu TK, Gutman AB. Renal function in Wilson’s disease. J Clin Invest. 1957;36:1107-1114. Pyeritz RE. Genetic heterogeneity in Wilson disease: lessons from rare alleles [editorial]. Ann Intern Med. 1997;127:70-72. Thomas GR, Forbes JR, Roberts EA, Walshe JM, Cox DW. The Wilson disease gene: spectrum of mutations and their conse-
Mayo Clin Proc, September 2003, Vol 78
40.
41. 42. 43.
44. 45. 46. 47. 48. 49. 50. 51. 52. 53. 54.
55. 56. 57. 58. 59. 60. 61. 62.
quences [published correction appears in Nat Genet. 1995;9:451]. Nat Genet. 1995;9:210-217. Perman JA, Werlin SL, Grand RJ, Watkins JB. Laboratory measures of copper metabolism in the differentiation of chronic active hepatitis and Wilson disease in children. J Pediatr. 1979;94:564568. Petrukhin K, Fischer SG, Pirastu M, et al. Mapping, cloning and genetic characterization of the region containing the Wilson disease gene. Nat Genet. 1993;5:338-343. Houwen RH, Juyn J, Hoogenraad TU, Ploos van Amstel JK, Berger R. H714Q mutation in Wilson disease is associated with late, neurological presentation. J Med Genet. 1995;32:480-482. Kemppainen R, Palatsi R, Kallioinen M, Oikarinen A. A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. J Invest Dermatol. 1997;108:3539. Maier-Dobersberger T, Ferenci P, Polli C, et al. Detection of the His1069Gln mutation in Wilson disease by rapid polymerase chain reaction. Ann Intern Med. 1997;127:21-26. Gaffney D, Walker JL, O’Donnell JG, et al. DNA-based presymptomatic diagnosis of Wilson disease. J Inherit Metab Dis. 1992;15:161-170. Chowrimootoo GF, Andoh J, Seymour CA. Western blot analysis in patients with hypocaeruloplasminaemia. QJM. 1997;90:197202. Walshe JM. Treatment of Wilson’s disease: the historical background. QJM. 1996;89:553-555. Durand F, Bernuau J, Giostra E, et al. Wilson’s disease with severe hepatic insufficiency: beneficial effects of early administration of D-penicillamine. Gut. 2001;48:849-852. Walshe JM, Dixon AK. Dangers of non-compliance in Wilson’s disease. Lancet. 1986;1:845-847. Van Caillie-Bertrand M, Degenhart HJ, Luijendijk I, Bouquet J, Sinaasappel M. Wilson’s disease: assessment of D-penicillamine treatment. Arch Dis Child. 1985;60:652-655. Santos Silva EE, Sarles J, Buts JP, Sokal EM. Successful medical treatment of severely decompensated Wilson disease. J Pediatr. 1996;128:285-287. Brewer GJ, Yuzbasiyan-Gurkan V. Wilson disease. Medicine (Baltimore). 1992;71:139-164. Dubois RS, Rodgerson DO, Hambidge KM. Treatment of Wilson’s disease with triethylene tetramine hydrochloride (Trientine). J Pediatr Gastroenterol Nutr. 1990;10:77-81. Dahlman T, Hartvig P, Lofholm M, Nordlinder H, Loof L, Westermark K. Long-term treatment of Wilson’s disease with triethylene tetramine dihydrochloride (trientine). QJM. 1995;88: 609-616. Brewer GJ, Yuzbasiyan-Gurkan V, Johnson V, Dick RD, Wang Y. Treatment of Wilson’s disease with zinc XII: dose regimen requirements. Am J Med Sci. 1993;305:199-202. Brewer GJ, Hill GM, Prasad AS, Cossack ZT, Rabbani P. Oral zinc therapy for Wilson’s disease. Ann Intern Med. 1983;99:314-319. Brewer GJ. Treatment of Wilson’s disease with zinc [letter]. J Lab Clin Med. 1999;134:322-324. Hoogenraad TU. Zinc treatment of Wilson’s disease [editorial]. J Lab Clin Med. 1998;132:240-241. Sternlieb I. Wilson’s disease: indications for liver transplants. Hepatology. 1984;4(1, suppl):15S-17S. Zitelli BJ, Malatack JJ, Gartner JC, et al. Orthotopic liver-transplantation in children with hepatic-based metabolic disease. Trans Proc. 1983;15:1284-1287. Bellary S, Hassanein T, Van Thiel DH. Liver transplantation for Wilson’s disease. J Hepatol. 1995;23:373-381. Irani AN, Malhi H, Slehria S, et al. Correction of liver disease following transplantation of normal rat hepatocytes into LongEvans Cinnamon rats modeling Wilson’s disease. Mol Ther. 2001; 3:302-309.
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