Disease-a-Month 60 (2014) 450–459
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Wilson’s disease: Etiology, diagnosis, and treatment Arif Dalvi, MD, MBA, Mahesh Padmanaban, MD
Genetics of Wilson’s disease Wilson’s disease (WD) is an inherited autosomal recessive disorder of copper balance. Kinnier Wilson in his original description recognized that it was a familial disease but did not consider it hereditary.1 A genetic origin was proposed by Hall in 1928, and an autosomal recessive inheritance was reported in 1953.2 By 1993, the specific chromosome and gene were localized.3 The offending gene, named ATP7B, is located on chromosome 13q14.3.4 The product of ATP7B is a cationtransporting P-type ATPase.4 This group of ATPases is involved in transporting metals into and out of cells by using energy stored in ATP.5 ATP7B is primarily located in the trans-Golgi Network (TGN) and in cytoplasmic vesicles.4 The structure of ATP7B is complex. It includes six copper-binding domains, a transduction domain involved in the transduction of the energy of ATP hydrolysis to cation transport, a cation channel and phosphorylation domain, a nucleotide-binding domain, and eight hydrophobic transmembrane sequences.5 Once copper has been bound, both secondary and tertiary structural changes take place, inducing phosphorylation. In the TGN, ATP7B mediates the incorporation of copper molecules into apoceruloplasmin to form ceruloplasmin. Ceruloplasmin, which is subsequently secreted from hepatocytes into the plasma, carries 90% of copper in plasma and is a source of copper for peripheral organs.4 The function of ATP7B is quite different in the cytoplasmic vesicles of hepatocytes. It acts to sequester excess copper and the vesicles are in turn excreted into bile.6 This is the major pathway of elimination of excess copper. When taking the function of ATP7B under consideration, one can begin to understand the laboratory values that are characteristic of WD (low ceruloplasmin and excess copper). Excessive intracellular copper leads to mitochondrial injury. This results in oxidative damage to hepatocytes and spillage of copper into blood, leading to further downstream events, including damage to the brain, kidney, and red blood cells.7 Though WD is thought to be an autosomal recessive disease, most individuals are compound heterozygotes, carrying different mutations on each allele encoding the WD gene.8 Over 500 distinct disease-causing mutations have been found, with some only in single families and others accounting for larger numbers of cases.5 Mutations generally result in loss of function. The most common mutation seen in the European population involves H1069Q in which histidine is replaced by glutamine in a highly conserved motif close to the ATP-binding region.9 Another common mutation seen predominantly in Asian populations is the R778L mutation.4 An http://dx.doi.org/10.1016/j.disamonth.2014.07.002 0011-5029/& 2014 Mosby, Inc. All rights reserved.
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intriguing aspect of WD is that individuals with the same genotype, e.g., monozygotic twins, can present with different phenotypes.7 Therefore, other genetic or environmental factors could influence the expression of the genotype, including dietary copper intake and the individual’s intrinsic capacity to handle copper overload.4 Awareness of the manifestations and treatment of WD is important both to primary care physicians and specialists in gastroenterology, neurology, psychiatry, and pediatrics. Wilson’s disease can cause severe disability and can be fatal if left untreated. With the protean and multisystem manifestations, it is easy to overlook the diagnosis. However, when diagnosed early, treatment options are available that can prevent or reverse many manifestations of WD and restore life expectancy to near normal.10
Pathology of Wilson’s disease The earliest lesions in WD are seen in the liver, the site of initial copper accumulation. The changes are nonspecific and include both macrosteatotic and microsteatotic changes within hepatocytes, often accompanied by cytoplasmic inclusions within nuclei.11 During the intermediate stage, lobular necrosis and periportal inflammation, swelling, and necrosis create a picture that may resemble autoimmune chronic hepatitis. Mallory bodies may be evident on biopsy. As WD progresses further, cirrhosis can develop. It may be of the micronodular type or a mixed macronodular–micronodular histological pattern.11 Central pontine myelinolysis (CPM) is often seen in WD. CPM may occur in the absence of specific etiological factors, such as electrolyte disturbances, and is much more common with the neurological form of WD.12 Ultrastructural abnormalities visualized with electron microscopy include large vacuoles, enlargement and separation of the mitochondrial inner and outer membranes, widening of the intercristal spaces, and increases in the density and granularity of the matrix. These findings on EM can be pathognomonic of WD if cholestasis is not present.11 Immunohistochemical stains for copper may demonstrate deposits of copper within the liver, renal tubular cells, and brain.11 On MRI and gross examination, the brain often is atrophic with white matter changes (hyperintense on T2 and hypointense on T1). Usually, the putamen, globus pallidus, caudate, thalamus, midbrain, pons, and cerebellum are most affected by copper overload. Histologically, there is in increase in the number of astrocytes within the gray matter. There are also signs of spongiform degeneration in more advanced cases with swollen glia and liquefaction. Opalski cells, which are thought to originate from degenerating astrocytes, are distinctive for WD. They are large cells with a fine granular cytoplasm and abnormal nuclei.11,12
Approach to diagnosis A high degree of suspicion is the key to early diagnosis (Table 1). Neurological symptoms in the form of tremor, dystonia, or parkinsonism and unexplained jaundice or abnormal liver
Table 1 Diagnostic considerations in Wilson's disease. WD should be considered in individuals with abnormal liver function of unclear etiology or movement disorders with early-onset or atypical presentations Assessment includes clinical evaluation, liver function tests, complete blood count, serum ceruloplasmin, and 24 h urinary copper excretion Liver biopsy to estimate liver copper content is the best biochemical evidence of WD Kayser–Fleischer rings should be sought by slit-lamp examination if not evident to clinical inspection First-degree relatives should be screened for WD When possible, genetic diagnosis should be used, especially in patients with indeterminate clinical and biochemical findings
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Table 2 Multisystem manifestations of Wilson’s disease. Hepatic Asymptomatic hepatomegaly Persistently elevated serum aminotransferases (ALT and AST) Acute and chronic hepatitis Cirrhosis (compensated and uncompensated) Fulminant hepatic failure Neurological Tremor (rest, postural, or mixed tremor) Parkinsonism Dystonia Chorea Dysarthria Sialorrhea Seizures Psychiatric Anxiety and depression Impulse control disorders Pseudobulbar affect Cognitive impairment Other organs Kayser–Fleischer rings Sunflower cataracts Hemolytic anemia Transient jaundice Pancreatitis Gallstones Nephrolithiasis Aminoaciduria Arthritis Cardiac arrhythmias Infertility
function tests in a child or young adult should raise suspicion of WD. Individuals younger than 55 years presenting with essential tremor or Parkinsonism merit screening for WD.13 Even though the yield is low, the cost of misdiagnosis is high. The clinical manifestations of WD are protean and it can present as a multisystem disorder adding to the diagnostic difficulty (Table 2). In one study, an average of six doctors, including specialists, were seen before the diagnosis of WD, with a mean diagnostic delay of 2 years.14 It is not unusual for families to have lost a child before WD is diagnosed in a younger sibling.15 Its diagnosis is based on identification of the clinical syndrome and confirmation in the form of laboratory tests and MRI. The most useful laboratory tests include measuring 24 h urinary copper excretion, serum ceruloplasmin, serum free copper, and hepatic copper concentration. An ophthalmologic exam utilizing a slit-lamp examination for detecting Kayser–Fleischer (KF) rings is also helpful. Screening individuals for mutations responsible for the disease can also serve as a confirmatory test.10 While genetic analysis is the gold standard for diagnosis, the presence of over 500 mutations makes this method impractical for routine clinical diagnosis. Siblings should be screened for the disease and followed up until adulthood, unless WD has been ruled out by genetic analysis. Magnetic resonance imaging (MRI) can provide an insight into the pathologic and anatomic correlates of clinical signs and symptoms in Wilson’s disease. Interval changes seen on follow-up MR images correlate well with clinical symptoms and are useful in evaluating treatment response. 24-h urinary copper excretion A urinary copper concentration greater than 100 μg/24 h is considered to be diagnostic for WD.16 Most symptomatic patients will have this level. However, a level in the range of 40–100 μg
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may also be present in some patients.10,11 In individuals heterozygous for WD, urinary copper excretion is rarely greater than 70 μg/24 h. Appropriate collection of the urine sample and avoiding copper contamination is important to obtain accurate estimates. Estimating 24-h urine copper excretion following a penicillamine challenge can also provide additional supportive evidence.17 This test involves administering 500 mg of penicillamine at baseline and at 12 h after starting the 24-h urine collection. If the final urinary copper concentration is greater than 1600 μg/24 h, then a diagnosis of Wilson’s disease is more likely than other liver diseases such as autoimmune hepatitis or acute liver failure. Serum copper It should be noted that measurement of serum (total) copper or indices like serum nonceruloplasmin-bound (free) copper is difficult to measure reliably and can be confusing to interpret due to confounding factors.18 Higher levels may also be found in acute liver failure or chronic cholestasis. Thus, serum copper levels have limited diagnostic utility.19 Serum ceruloplasmin Ceruloplasmin is a copper-carrying protein that is bound to 90% of circulating copper in normal individuals. The normal concentration of ceruloplasmin is 20–40 mg/dL, and a level below 20 mg/dL is suggestive of WD, although not diagnostic by itself. Low levels can be found in 1% of normal individuals, 10% of heterozygous carriers, and in patients with other disorders such as copper deficiency, Menkes disease, hereditary hypoceruloplasminemia, and nephrotic syndrome. About 20% of WD patients will have normal levels of serum ceruloplasmin.11
Liver biopsy Histological findings include steatosis, glycogenated nuclei in hepatocytes, focal necrosis of hepatocytes, fibrosis, and cirrhosis. Usually, the cirrhosis seen in WD has a macronodular pattern. Marked hepatocellular disruption and apoptotic and necrotic changes against a background of fibrosis can be seen in acute liver failure due to WD. Electron microscopy shows mitochondrial changes, including dilatation of the tips of mitochondrial cristae. As the disease progresses, dense lysosomal deposits of copper and copper metallothionein may be seen.11,12 Hepatic copper concentration In most patients, the liver has copper content more than 250 μg/g dry weight and may even exceed 3000 μg/g dry weight. Normal levels are less than 50 μg/g dry weight. Hepatic copper concentration may be lower than 50 μg/g dry weight in up to 20% of patients, especially those with predominantly neuropsychiatric involvement. Lowering the diagnostic threshold to 75 μg/g can increase the sensitivity by about 13%.20 Kayser–Fleischer rings KF rings are a common accompaniment of neurological WD.21 The presence of KF rings in combination with low serum ceruloplasmin and typical neurological manifestations is diagnostic of WD.22 They represent a pathophysiology in which free copper has been released into the circulation and has started to accumulate in tissues, including the cornea. Almost all patients with neuropsychiatric symptoms will show KF rings, whereas about 50–60% of patients with hepatic WD will have this manifestation.23 KF rings are less common in children.24 The rings are seen to diminish with long-term chelation therapy. Slit-lamp examination may be required to identify KF rings in early disease or in patients with a dark iris.
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Genetic testing Given the protean variations in the clinical and biochemical features of WD, mutation analysis may be required to confirm the diagnosis. Detection of a mutation confirms the diagnosis; however, a negative result cannot exclude the diagnosis of WD. A disease-causing mutation may not be found in about 20% of patients with clinically definite WD.8 The utility of genetic testing is higher in ethnicities that have a predominant mutation, and it is less useful in other geographical areas. In clinical practice, genetic testing is mainly limited to the screening of first-degree relatives of WD patients. The probability of finding a homozygote is 25% in siblings and 0.5% in the children.11 MRI The classic radiological sign of WB is the “face of the giant panda” seen in the midbrain.25 This consists of high signal intensity in the tegmentum, preservation of signal intensity of the lateral portion of the pars reticulata of the substantia nigra and red nucleus, and hypointensity of the superior colliculus. In addition, a “face of panda cub” may be seen within the dorsal part of pons.25,26 In a longitudinal study the following MR observations were noted exclusively in WD: “Face-of-giant-panda” sign (14.3%), tectal plate hyperintensity (75%), central pontine myelinolysis-like abnormalities (62.5%), and concurrent signal changes in basal ganglia, thalamus, and brainstem (55.3%).27 However, it should be noted that the MRI findings in WD are neither sensitive nor specific and must be supplemented by laboratory testing. Diagnostic index In 2001, a diagnostic index was developed using the following parameters: 24-h urinary copper, hepatic copper concentration, ceruloplasmin, presence of ATP7B mutations, presence of KF rings, neuropsychiatric symptoms, brain MRI findings compatible with copper deposition, and hemolytic anemia (Table 3). After assigning a score from 0 to 2 for each parameter, the final score indicates a likelihood of the diagnosis (greater than or equal to 4, certain; 2–3, likely; and 0–1, unlikely).28 However, this scoring system has not been prospectively evaluated. Formal
Table 3 Scoring system for the diagnosis of Wilson’s disease.28 Symptoms and tests Kayser–Fleischer ring Neurological symptoms or MRI findings Coombs-negative hemolytic anemia Urinary copper 1–2 upper limit of normal (ULN) 4 2 ULN Normal, but 45 ULN Liver copper content 1–5 ULN 4 5 ULN Normal Rhodamine staining (if liver Cu is not available) Positive Serum ceruloplasmin (mg/dL) 10–20 o10 Mutation analysis Disease-causing mutations on both chromosomes Disease-causing mutations on one chromosome
Points 2 2 1 1 2 2 1 2 1 1 1 2 4 1
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guidelines have also been proposed for the diagnosis and treatment of WD by the American Association for the Study of Liver Diseases.19,29
Treatment The treatment of Wilson’s disease incorporates two aspects: removal of copper deposits from various organs and symptomatic therapy.10,30 The copper deposits can be extracted by chelating agents, which create a negative copper balance. The first such treatment was with British AntiLewisite (BAL) or dimercaprol, which had been originally developed by British biochemists as an antidote to Lewisite, an arsenic-based chemical warfare agent. The introduction of its use to reduce copper overload by Denny-Brown and Porter31 represents one of the first successful treatments for a neurological disease. However, use of BAL was limited due to the fact that it required intramuscular administration and had significant toxicity. Walshe32 was the first to use oral penicillamine, based on his observation that the chemical structure of this metabolite of penicillin could permit it to act as a chelating agent. The discovery that zinc acetate reduces the dietary absorption of copper has led to its use particularly in the maintenance phase of treatment for WD. Other treatment options include trientine and ammonium tetrathiomolybdate. Orthoptic liver transplantation is an option in patients who have suffered significant hepatotoxicity.11 Symptomatic treatment includes the management of hepatotoxicity and portal hypertension as well as treatment of neurological symptoms such as tremor and dystonia. The key to successful management of WD is early treatment so that significant end-organ damage can be prevented. Close follow-up of patients is required to ensure early detection of liver damage as well as to monitor for drug toxicity from chelating agents. The restriction of dietary copper has a supplementary role by reducing the burden of copper overload.7 Table 4 summarizes the current medical treatment of WD. Penicillamine Penicillamine was the first oral agent used to treat WD.32 Its name is derived from the observation that it is a breakdown product of penicillin. However, in its current form it is a synthetic product, hence contamination with penicillin is not a concern. Its molecular structure has a free sulfhydryl group, which is the basis for its ability to chelate copper. Penicillamine can also induce metallothionein, a cysteine-rich protein that acts as an endogenous chelator of metals. Thus, in addition to enhancing urinary copper excretion, it can also lead to the sequestration of free intracellular copper.32 Penicillamine improves liver disease as well as neurological symptoms. Patients with severe liver disease may respond to penicillamine with improvement in laboratory values, such as high bilirubin and prolonged prothrombin time as well as an improvement in clinical features such as ascites. If a rapid improvement is not shown, the patient should be listed for urgent liver transplantation. Neurological symptoms such as parkinsonism and tremor also improve, and imaging studies such as cerebral MRI show improvement as well. However, in 20–50% of cases, an initial deterioration in neurological status may occur.33 This has led Brewer34 to suggest that penicillamine should not be used in the initial treatment of WD with a neurological presentation. However, Walshe35 has published extensive experience showing that even in neurological WD, penicillamine can be an effective treatment with the caveat that close followup and monitoring of patients is required. Close monitoring of the patient is recommended to assess for effect as well as to monitor for side effects. The latter include fever, rash, bone marrow suppression, and proteinuria. A lupuslike syndrome may also be seen. Dermatological complications include elastosis perforans serpiginosa36and aphthous stomatitis.11 In its original formulation, the racemic mixture was used, which interfered with the action of pyridoxine, requiring routine supplementation with oral pyridoxine. The present formulation is less likely to have this effect. Nonetheless, pyridoxine
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Table 4 Medical treatment of Wilson’s disease. Drug
Mechanism
Penicillamine
Chelation through sulfhydryl group
Trientine
Zinc
Ammonium tetrathiomolybdate
a b
Adult dosing
Side effects
Comments
Neurological Highly effective with deterioration at quick response but initiation, bone needs close marrow suppression, monitoring and lupus-like syndrome More expensive and Hemosiderosis and Chelation through Initial dose: 750– somewhat a anemia. Neurological nitrogen groups 1500 mg/day, weaker chelator deterioration is less maintenance dose: b than penicillamine common 750–1500 mg/day but with fewer side effects Less commonly used Sequesters copper in Maintenance dose: 50– Gastrointestinal side as initial therapy enterocytes 150 mg/day effects that are less with zinc acetate compared to zinc sulfate Lower incidence of Not FDA approved Complexes with dietary 20 mg three times a neurological day with meals and copper when given deterioration 20 mg three times a with meals and with day between meals free copper and serum albumin when given between meals Initial dose: 250– 500 mg/day,a maintenance dose: 500–1500 mg/dayb
Administer with pyridoxine 25 mg/day. Chelation therapy doses are guided by monitoring urinary excretion of copper.
at a dose of 25–50 mg/day is usually prescribed as a prophylactic measure especially in children, pregnant women, and patients with comorbid illness.37 Trientine Trientine also acts as a chelator, promoting the urinary excretion of copper. It has a polyamine structure that allows it to bind with copper by forming stable complexes with its four nitrogen groups. Although commonly regarded as a weaker chelator of copper than penicillamine, it has also been associated with fewer side effects. Unlike penicillamine, trientine rarely causes pancytopenia or hypersensitivity reactions and may be somewhat less likely to be associated with neurological deterioration.38 Thus, it is also considered first-line therapy for WD39 and may be used as a substitute for penicillamine when necessary.40 It can be successfully combined with zinc acetate as maintenance therapy.39 Neurological worsening is also described with trientine, but is less frequent and is of the order of about 25% of cases.7 Hemosiderosis and anemia may occur after excessive copper chelation.41 Zinc Zinc acts by inducing metallothionein in hepatocytes and enterocytes. Oral zinc binds to the metallothionein, trapping it within the enterocytes. Metallothionein has a higher affinity for copper than zinc and thus binds to dietary copper, allowing it to be sequestered within enterocytes. This sequestered copper is excreted in the intestinal lumen as the enterocytes are sloughed.42 Zinc also induces hepatic metallothionein, allowing it to complex copper in the hepatocytes in a nontoxic form.43 Zinc acetate can be used both in the presymptomatic phase and in the maintenance phase of therapy for WD following an initial phase of more aggressive decoppering using chelating agents.39 However, it is felt that it may not be as effective as
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chelating agents as an initial therapy for WD.44 Toxicity with zinc is rare, and it is the preferred treatment in pregnancy for patients with WD.42
Ammonium tetrathiomolybdate Ammonium tetrathiomolybdate exerts a chelating action by forming a complex with copper and protein. When taken with meals, it forms complexes with dietary copper as well as copper secreted into the intestine, thus reducing copper absorption. When taken between meals, it is absorbed and complexes copper in the blood with albumin. This complex is metabolized by the liver and is excreted in bile.45 According to Brewer, neurological deterioration is less common with this medication compared to penicillamine or trientine. A randomized study comparing ammonium tetrathiomolybdate with trientine showed that one of 27 patients showed neurological decline on this drug compared with 5 of 27 on trientine.38 Anemia or leukopenia may occur as a side effect. However, the medication is not yet FDA approved.
Symptomatic treatment This includes treatment of tremor and dystonia in neurological WD. Dystonic symptoms may respond to baclofen or benzodiazepines. Clonazepam is usually preferred to shorter-acting benzodiazepines. Anticholinergics such as trihexyphenidyl may also be tried. Parkinsonism may be treated with levodopa or dopamine agonists, although the response tends to be poor. Postural tremor may respond to medications used to treat essential tremor, such as propranolol and primidone.11
Dietary modifications Shellfish and liver are especially rich in copper and their intake should be avoided. Animal feeds contain a high amount of copper, which is stored in the liver. Thus, particularly in the decoppering phase, liver or liver preparations should be avoided. Shellfish also are rich in copper, and their use should be avoided in the initial phase of treatment and minimized in the maintenance phase.11,46 Other copper-rich foods include chocolate, nuts, or mushrooms but have a copper content that is not high enough to necessitate strict restriction. A vegetarian diet has been found to be beneficial in the maintenance phase in anecdotal reports.47 It should be kept in mind that in some areas, drinking water is a source of concern, and if copper levels exceed 0.1 ppm, then bottled water should be preferred.11 Abstinence from alcohol is recommended to avoid an additional toxic insult to the liver.
Monitoring treatment Close follow-up is essential both to ensure that the treatment is effective and to monitor for side effects. Repeated neurological examinations, monitoring of liver function tests, complete blood counts, and urinary copper measurements should be carried out. During the initial chelation therapy, 24-h urinary copper excretion of 3–8 μmol/24 h (200–500 μg/24 h) reflects adequate treatment. During the maintenance phase with zinc, the 24-h urinary copper excretion should be less than 2.0 μmol/24 h (125 μg/24 h). Higher levels indicate the need for higher zinc doses or the resumption of a chelating agent. Measurement of non-ceruloplasmin-bound copper is a less reliable measure as it is measured by an immunological assay rather than an enzymatic assay, but target levels of 50–150 μg/L are considered to reflect adequate treatment.11
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Liver transplantation Liver transplantation is indicated for WD patients with fulminant hepatic failure as the initial presentation of disease, most commonly in the second decade of life, or those with medically intractable WD with severe hepatic insufficiency, most commonly in the third and fourth decades.48 While the transplant only partially corrects the defective metabolism in patients with Wilson’s disease, it does convert the copper kinetics of a homozygote to that of a heterozygote. Thus, transplantation can effectively be curative but has substantial risks both related to the operative procedure and the subsequent immunotherapy that is required.49 The transplantation can be through a cadaveric donor or a living donor transplant, even if the donor is a heterozygous carrier. Liver transplantation is also indicated in patients who are refractory to medical therapy. 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Wilson’s disease: Etiology, diagnosis, and treatment Arif Dalvi, MD, MBA, Mahesh Padmanaban, MD
Genetics of Wilson’s disease Wilson’s disease (WD) is an inherited autosomal recessive disorder of copper balance. Kinnier Wilson in his original description recognized that it was a familial disease but did not consider it hereditary.1 A genetic origin was proposed by Hall in 1928, and an autosomal recessive inheritance was reported in 1953.2 By 1993, the specific chromosome and gene were localized.3 The offending gene, named ATP7B, is located on chromosome 13q14.3.4 The product of ATP7B is a cationtransporting P-type ATPase.4 This group of ATPases is involved in transporting metals into and out of cells by using energy stored in ATP.5 ATP7B is primarily located in the trans-Golgi Network (TGN) and in cytoplasmic vesicles.4 The structure of ATP7B is complex. It includes six copper-binding domains, a transduction domain involved in the transduction of the energy of ATP hydrolysis to cation transport, a cation channel and phosphorylation domain, a nucleotide-binding domain, and eight hydrophobic transmembrane sequences.5 Once copper has been bound, both secondary and tertiary structural changes take place, inducing phosphorylation. In the TGN, ATP7B mediates the incorporation of copper molecules into apoceruloplasmin to form ceruloplasmin. Ceruloplasmin, which is subsequently secreted from hepatocytes into the plasma, carries 90% of copper in plasma and is a source of copper for peripheral organs.4 The function of ATP7B is quite different in the cytoplasmic vesicles of hepatocytes. It acts to sequester excess copper and the vesicles are in turn excreted into bile.6 This is the major pathway of elimination of excess copper. When taking the function of ATP7B under consideration, one can begin to understand the laboratory values that are characteristic of WD (low ceruloplasmin and excess copper). Excessive intracellular copper leads to mitochondrial injury. This results in oxidative damage to hepatocytes and spillage of copper into blood, leading to further downstream events, including damage to the brain, kidney, and red blood cells.7 Though WD is thought to be an autosomal recessive disease, most individuals are compound heterozygotes, carrying different mutations on each allele encoding the WD gene.8 Over 500 distinct disease-causing mutations have been found, with some only in single families and others accounting for larger numbers of cases.5 Mutations generally result in loss of function. The most common mutation seen in the European population involves H1069Q in which histidine is replaced by glutamine in a highly conserved motif close to the ATP-binding region.9 Another common mutation seen predominantly in Asian populations is the R778L mutation.4 An http://dx.doi.org/10.1016/j.disamonth.2014.07.002 0011-5029/& 2014 Mosby, Inc. All rights reserved.
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intriguing aspect of WD is that individuals with the same genotype, e.g., monozygotic twins, can present with different phenotypes.7 Therefore, other genetic or environmental factors could influence the expression of the genotype, including dietary copper intake and the individual’s intrinsic capacity to handle copper overload.4 Awareness of the manifestations and treatment of WD is important both to primary care physicians and specialists in gastroenterology, neurology, psychiatry, and pediatrics. Wilson’s disease can cause severe disability and can be fatal if left untreated. With the protean and multisystem manifestations, it is easy to overlook the diagnosis. However, when diagnosed early, treatment options are available that can prevent or reverse many manifestations of WD and restore life expectancy to near normal.10
Pathology of Wilson’s disease The earliest lesions in WD are seen in the liver, the site of initial copper accumulation. The changes are nonspecific and include both macrosteatotic and microsteatotic changes within hepatocytes, often accompanied by cytoplasmic inclusions within nuclei.11 During the intermediate stage, lobular necrosis and periportal inflammation, swelling, and necrosis create a picture that may resemble autoimmune chronic hepatitis. Mallory bodies may be evident on biopsy. As WD progresses further, cirrhosis can develop. It may be of the micronodular type or a mixed macronodular–micronodular histological pattern.11 Central pontine myelinolysis (CPM) is often seen in WD. CPM may occur in the absence of specific etiological factors, such as electrolyte disturbances, and is much more common with the neurological form of WD.12 Ultrastructural abnormalities visualized with electron microscopy include large vacuoles, enlargement and separation of the mitochondrial inner and outer membranes, widening of the intercristal spaces, and increases in the density and granularity of the matrix. These findings on EM can be pathognomonic of WD if cholestasis is not present.11 Immunohistochemical stains for copper may demonstrate deposits of copper within the liver, renal tubular cells, and brain.11 On MRI and gross examination, the brain often is atrophic with white matter changes (hyperintense on T2 and hypointense on T1). Usually, the putamen, globus pallidus, caudate, thalamus, midbrain, pons, and cerebellum are most affected by copper overload. Histologically, there is in increase in the number of astrocytes within the gray matter. There are also signs of spongiform degeneration in more advanced cases with swollen glia and liquefaction. Opalski cells, which are thought to originate from degenerating astrocytes, are distinctive for WD. They are large cells with a fine granular cytoplasm and abnormal nuclei.11,12
Approach to diagnosis A high degree of suspicion is the key to early diagnosis (Table 1). Neurological symptoms in the form of tremor, dystonia, or parkinsonism and unexplained jaundice or abnormal liver
Table 1 Diagnostic considerations in Wilson's disease. WD should be considered in individuals with abnormal liver function of unclear etiology or movement disorders with early-onset or atypical presentations Assessment includes clinical evaluation, liver function tests, complete blood count, serum ceruloplasmin, and 24 h urinary copper excretion Liver biopsy to estimate liver copper content is the best biochemical evidence of WD Kayser–Fleischer rings should be sought by slit-lamp examination if not evident to clinical inspection First-degree relatives should be screened for WD When possible, genetic diagnosis should be used, especially in patients with indeterminate clinical and biochemical findings
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Table 2 Multisystem manifestations of Wilson’s disease. Hepatic Asymptomatic hepatomegaly Persistently elevated serum aminotransferases (ALT and AST) Acute and chronic hepatitis Cirrhosis (compensated and uncompensated) Fulminant hepatic failure Neurological Tremor (rest, postural, or mixed tremor) Parkinsonism Dystonia Chorea Dysarthria Sialorrhea Seizures Psychiatric Anxiety and depression Impulse control disorders Pseudobulbar affect Cognitive impairment Other organs Kayser–Fleischer rings Sunflower cataracts Hemolytic anemia Transient jaundice Pancreatitis Gallstones Nephrolithiasis Aminoaciduria Arthritis Cardiac arrhythmias Infertility
function tests in a child or young adult should raise suspicion of WD. Individuals younger than 55 years presenting with essential tremor or Parkinsonism merit screening for WD.13 Even though the yield is low, the cost of misdiagnosis is high. The clinical manifestations of WD are protean and it can present as a multisystem disorder adding to the diagnostic difficulty (Table 2). In one study, an average of six doctors, including specialists, were seen before the diagnosis of WD, with a mean diagnostic delay of 2 years.14 It is not unusual for families to have lost a child before WD is diagnosed in a younger sibling.15 Its diagnosis is based on identification of the clinical syndrome and confirmation in the form of laboratory tests and MRI. The most useful laboratory tests include measuring 24 h urinary copper excretion, serum ceruloplasmin, serum free copper, and hepatic copper concentration. An ophthalmologic exam utilizing a slit-lamp examination for detecting Kayser–Fleischer (KF) rings is also helpful. Screening individuals for mutations responsible for the disease can also serve as a confirmatory test.10 While genetic analysis is the gold standard for diagnosis, the presence of over 500 mutations makes this method impractical for routine clinical diagnosis. Siblings should be screened for the disease and followed up until adulthood, unless WD has been ruled out by genetic analysis. Magnetic resonance imaging (MRI) can provide an insight into the pathologic and anatomic correlates of clinical signs and symptoms in Wilson’s disease. Interval changes seen on follow-up MR images correlate well with clinical symptoms and are useful in evaluating treatment response. 24-h urinary copper excretion A urinary copper concentration greater than 100 μg/24 h is considered to be diagnostic for WD.16 Most symptomatic patients will have this level. However, a level in the range of 40–100 μg
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may also be present in some patients.10,11 In individuals heterozygous for WD, urinary copper excretion is rarely greater than 70 μg/24 h. Appropriate collection of the urine sample and avoiding copper contamination is important to obtain accurate estimates. Estimating 24-h urine copper excretion following a penicillamine challenge can also provide additional supportive evidence.17 This test involves administering 500 mg of penicillamine at baseline and at 12 h after starting the 24-h urine collection. If the final urinary copper concentration is greater than 1600 μg/24 h, then a diagnosis of Wilson’s disease is more likely than other liver diseases such as autoimmune hepatitis or acute liver failure. Serum copper It should be noted that measurement of serum (total) copper or indices like serum nonceruloplasmin-bound (free) copper is difficult to measure reliably and can be confusing to interpret due to confounding factors.18 Higher levels may also be found in acute liver failure or chronic cholestasis. Thus, serum copper levels have limited diagnostic utility.19 Serum ceruloplasmin Ceruloplasmin is a copper-carrying protein that is bound to 90% of circulating copper in normal individuals. The normal concentration of ceruloplasmin is 20–40 mg/dL, and a level below 20 mg/dL is suggestive of WD, although not diagnostic by itself. Low levels can be found in 1% of normal individuals, 10% of heterozygous carriers, and in patients with other disorders such as copper deficiency, Menkes disease, hereditary hypoceruloplasminemia, and nephrotic syndrome. About 20% of WD patients will have normal levels of serum ceruloplasmin.11
Liver biopsy Histological findings include steatosis, glycogenated nuclei in hepatocytes, focal necrosis of hepatocytes, fibrosis, and cirrhosis. Usually, the cirrhosis seen in WD has a macronodular pattern. Marked hepatocellular disruption and apoptotic and necrotic changes against a background of fibrosis can be seen in acute liver failure due to WD. Electron microscopy shows mitochondrial changes, including dilatation of the tips of mitochondrial cristae. As the disease progresses, dense lysosomal deposits of copper and copper metallothionein may be seen.11,12 Hepatic copper concentration In most patients, the liver has copper content more than 250 μg/g dry weight and may even exceed 3000 μg/g dry weight. Normal levels are less than 50 μg/g dry weight. Hepatic copper concentration may be lower than 50 μg/g dry weight in up to 20% of patients, especially those with predominantly neuropsychiatric involvement. Lowering the diagnostic threshold to 75 μg/g can increase the sensitivity by about 13%.20 Kayser–Fleischer rings KF rings are a common accompaniment of neurological WD.21 The presence of KF rings in combination with low serum ceruloplasmin and typical neurological manifestations is diagnostic of WD.22 They represent a pathophysiology in which free copper has been released into the circulation and has started to accumulate in tissues, including the cornea. Almost all patients with neuropsychiatric symptoms will show KF rings, whereas about 50–60% of patients with hepatic WD will have this manifestation.23 KF rings are less common in children.24 The rings are seen to diminish with long-term chelation therapy. Slit-lamp examination may be required to identify KF rings in early disease or in patients with a dark iris.
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Genetic testing Given the protean variations in the clinical and biochemical features of WD, mutation analysis may be required to confirm the diagnosis. Detection of a mutation confirms the diagnosis; however, a negative result cannot exclude the diagnosis of WD. A disease-causing mutation may not be found in about 20% of patients with clinically definite WD.8 The utility of genetic testing is higher in ethnicities that have a predominant mutation, and it is less useful in other geographical areas. In clinical practice, genetic testing is mainly limited to the screening of first-degree relatives of WD patients. The probability of finding a homozygote is 25% in siblings and 0.5% in the children.11 MRI The classic radiological sign of WB is the “face of the giant panda” seen in the midbrain.25 This consists of high signal intensity in the tegmentum, preservation of signal intensity of the lateral portion of the pars reticulata of the substantia nigra and red nucleus, and hypointensity of the superior colliculus. In addition, a “face of panda cub” may be seen within the dorsal part of pons.25,26 In a longitudinal study the following MR observations were noted exclusively in WD: “Face-of-giant-panda” sign (14.3%), tectal plate hyperintensity (75%), central pontine myelinolysis-like abnormalities (62.5%), and concurrent signal changes in basal ganglia, thalamus, and brainstem (55.3%).27 However, it should be noted that the MRI findings in WD are neither sensitive nor specific and must be supplemented by laboratory testing. Diagnostic index In 2001, a diagnostic index was developed using the following parameters: 24-h urinary copper, hepatic copper concentration, ceruloplasmin, presence of ATP7B mutations, presence of KF rings, neuropsychiatric symptoms, brain MRI findings compatible with copper deposition, and hemolytic anemia (Table 3). After assigning a score from 0 to 2 for each parameter, the final score indicates a likelihood of the diagnosis (greater than or equal to 4, certain; 2–3, likely; and 0–1, unlikely).28 However, this scoring system has not been prospectively evaluated. Formal
Table 3 Scoring system for the diagnosis of Wilson’s disease.28 Symptoms and tests Kayser–Fleischer ring Neurological symptoms or MRI findings Coombs-negative hemolytic anemia Urinary copper 1–2 upper limit of normal (ULN) 4 2 ULN Normal, but 45 ULN Liver copper content 1–5 ULN 4 5 ULN Normal Rhodamine staining (if liver Cu is not available) Positive Serum ceruloplasmin (mg/dL) 10–20 o10 Mutation analysis Disease-causing mutations on both chromosomes Disease-causing mutations on one chromosome
Points 2 2 1 1 2 2 1 2 1 1 1 2 4 1
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guidelines have also been proposed for the diagnosis and treatment of WD by the American Association for the Study of Liver Diseases.19,29
Treatment The treatment of Wilson’s disease incorporates two aspects: removal of copper deposits from various organs and symptomatic therapy.10,30 The copper deposits can be extracted by chelating agents, which create a negative copper balance. The first such treatment was with British AntiLewisite (BAL) or dimercaprol, which had been originally developed by British biochemists as an antidote to Lewisite, an arsenic-based chemical warfare agent. The introduction of its use to reduce copper overload by Denny-Brown and Porter31 represents one of the first successful treatments for a neurological disease. However, use of BAL was limited due to the fact that it required intramuscular administration and had significant toxicity. Walshe32 was the first to use oral penicillamine, based on his observation that the chemical structure of this metabolite of penicillin could permit it to act as a chelating agent. The discovery that zinc acetate reduces the dietary absorption of copper has led to its use particularly in the maintenance phase of treatment for WD. Other treatment options include trientine and ammonium tetrathiomolybdate. Orthoptic liver transplantation is an option in patients who have suffered significant hepatotoxicity.11 Symptomatic treatment includes the management of hepatotoxicity and portal hypertension as well as treatment of neurological symptoms such as tremor and dystonia. The key to successful management of WD is early treatment so that significant end-organ damage can be prevented. Close follow-up of patients is required to ensure early detection of liver damage as well as to monitor for drug toxicity from chelating agents. The restriction of dietary copper has a supplementary role by reducing the burden of copper overload.7 Table 4 summarizes the current medical treatment of WD. Penicillamine Penicillamine was the first oral agent used to treat WD.32 Its name is derived from the observation that it is a breakdown product of penicillin. However, in its current form it is a synthetic product, hence contamination with penicillin is not a concern. Its molecular structure has a free sulfhydryl group, which is the basis for its ability to chelate copper. Penicillamine can also induce metallothionein, a cysteine-rich protein that acts as an endogenous chelator of metals. Thus, in addition to enhancing urinary copper excretion, it can also lead to the sequestration of free intracellular copper.32 Penicillamine improves liver disease as well as neurological symptoms. Patients with severe liver disease may respond to penicillamine with improvement in laboratory values, such as high bilirubin and prolonged prothrombin time as well as an improvement in clinical features such as ascites. If a rapid improvement is not shown, the patient should be listed for urgent liver transplantation. Neurological symptoms such as parkinsonism and tremor also improve, and imaging studies such as cerebral MRI show improvement as well. However, in 20–50% of cases, an initial deterioration in neurological status may occur.33 This has led Brewer34 to suggest that penicillamine should not be used in the initial treatment of WD with a neurological presentation. However, Walshe35 has published extensive experience showing that even in neurological WD, penicillamine can be an effective treatment with the caveat that close followup and monitoring of patients is required. Close monitoring of the patient is recommended to assess for effect as well as to monitor for side effects. The latter include fever, rash, bone marrow suppression, and proteinuria. A lupuslike syndrome may also be seen. Dermatological complications include elastosis perforans serpiginosa36and aphthous stomatitis.11 In its original formulation, the racemic mixture was used, which interfered with the action of pyridoxine, requiring routine supplementation with oral pyridoxine. The present formulation is less likely to have this effect. Nonetheless, pyridoxine
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Table 4 Medical treatment of Wilson’s disease. Drug
Mechanism
Penicillamine
Chelation through sulfhydryl group
Trientine
Zinc
Ammonium tetrathiomolybdate
a b
Adult dosing
Side effects
Comments
Neurological Highly effective with deterioration at quick response but initiation, bone needs close marrow suppression, monitoring and lupus-like syndrome More expensive and Hemosiderosis and Chelation through Initial dose: 750– somewhat a anemia. Neurological nitrogen groups 1500 mg/day, weaker chelator deterioration is less maintenance dose: b than penicillamine common 750–1500 mg/day but with fewer side effects Less commonly used Sequesters copper in Maintenance dose: 50– Gastrointestinal side as initial therapy enterocytes 150 mg/day effects that are less with zinc acetate compared to zinc sulfate Lower incidence of Not FDA approved Complexes with dietary 20 mg three times a neurological day with meals and copper when given deterioration 20 mg three times a with meals and with day between meals free copper and serum albumin when given between meals Initial dose: 250– 500 mg/day,a maintenance dose: 500–1500 mg/dayb
Administer with pyridoxine 25 mg/day. Chelation therapy doses are guided by monitoring urinary excretion of copper.
at a dose of 25–50 mg/day is usually prescribed as a prophylactic measure especially in children, pregnant women, and patients with comorbid illness.37 Trientine Trientine also acts as a chelator, promoting the urinary excretion of copper. It has a polyamine structure that allows it to bind with copper by forming stable complexes with its four nitrogen groups. Although commonly regarded as a weaker chelator of copper than penicillamine, it has also been associated with fewer side effects. Unlike penicillamine, trientine rarely causes pancytopenia or hypersensitivity reactions and may be somewhat less likely to be associated with neurological deterioration.38 Thus, it is also considered first-line therapy for WD39 and may be used as a substitute for penicillamine when necessary.40 It can be successfully combined with zinc acetate as maintenance therapy.39 Neurological worsening is also described with trientine, but is less frequent and is of the order of about 25% of cases.7 Hemosiderosis and anemia may occur after excessive copper chelation.41 Zinc Zinc acts by inducing metallothionein in hepatocytes and enterocytes. Oral zinc binds to the metallothionein, trapping it within the enterocytes. Metallothionein has a higher affinity for copper than zinc and thus binds to dietary copper, allowing it to be sequestered within enterocytes. This sequestered copper is excreted in the intestinal lumen as the enterocytes are sloughed.42 Zinc also induces hepatic metallothionein, allowing it to complex copper in the hepatocytes in a nontoxic form.43 Zinc acetate can be used both in the presymptomatic phase and in the maintenance phase of therapy for WD following an initial phase of more aggressive decoppering using chelating agents.39 However, it is felt that it may not be as effective as
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chelating agents as an initial therapy for WD.44 Toxicity with zinc is rare, and it is the preferred treatment in pregnancy for patients with WD.42
Ammonium tetrathiomolybdate Ammonium tetrathiomolybdate exerts a chelating action by forming a complex with copper and protein. When taken with meals, it forms complexes with dietary copper as well as copper secreted into the intestine, thus reducing copper absorption. When taken between meals, it is absorbed and complexes copper in the blood with albumin. This complex is metabolized by the liver and is excreted in bile.45 According to Brewer, neurological deterioration is less common with this medication compared to penicillamine or trientine. A randomized study comparing ammonium tetrathiomolybdate with trientine showed that one of 27 patients showed neurological decline on this drug compared with 5 of 27 on trientine.38 Anemia or leukopenia may occur as a side effect. However, the medication is not yet FDA approved.
Symptomatic treatment This includes treatment of tremor and dystonia in neurological WD. Dystonic symptoms may respond to baclofen or benzodiazepines. Clonazepam is usually preferred to shorter-acting benzodiazepines. Anticholinergics such as trihexyphenidyl may also be tried. Parkinsonism may be treated with levodopa or dopamine agonists, although the response tends to be poor. Postural tremor may respond to medications used to treat essential tremor, such as propranolol and primidone.11
Dietary modifications Shellfish and liver are especially rich in copper and their intake should be avoided. Animal feeds contain a high amount of copper, which is stored in the liver. Thus, particularly in the decoppering phase, liver or liver preparations should be avoided. Shellfish also are rich in copper, and their use should be avoided in the initial phase of treatment and minimized in the maintenance phase.11,46 Other copper-rich foods include chocolate, nuts, or mushrooms but have a copper content that is not high enough to necessitate strict restriction. A vegetarian diet has been found to be beneficial in the maintenance phase in anecdotal reports.47 It should be kept in mind that in some areas, drinking water is a source of concern, and if copper levels exceed 0.1 ppm, then bottled water should be preferred.11 Abstinence from alcohol is recommended to avoid an additional toxic insult to the liver.
Monitoring treatment Close follow-up is essential both to ensure that the treatment is effective and to monitor for side effects. Repeated neurological examinations, monitoring of liver function tests, complete blood counts, and urinary copper measurements should be carried out. During the initial chelation therapy, 24-h urinary copper excretion of 3–8 μmol/24 h (200–500 μg/24 h) reflects adequate treatment. During the maintenance phase with zinc, the 24-h urinary copper excretion should be less than 2.0 μmol/24 h (125 μg/24 h). Higher levels indicate the need for higher zinc doses or the resumption of a chelating agent. Measurement of non-ceruloplasmin-bound copper is a less reliable measure as it is measured by an immunological assay rather than an enzymatic assay, but target levels of 50–150 μg/L are considered to reflect adequate treatment.11
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Liver transplantation Liver transplantation is indicated for WD patients with fulminant hepatic failure as the initial presentation of disease, most commonly in the second decade of life, or those with medically intractable WD with severe hepatic insufficiency, most commonly in the third and fourth decades.48 While the transplant only partially corrects the defective metabolism in patients with Wilson’s disease, it does convert the copper kinetics of a homozygote to that of a heterozygote. Thus, transplantation can effectively be curative but has substantial risks both related to the operative procedure and the subsequent immunotherapy that is required.49 The transplantation can be through a cadaveric donor or a living donor transplant, even if the donor is a heterozygous carrier. Liver transplantation is also indicated in patients who are refractory to medical therapy. 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