Wilson Disease

An Overview and Approach to Management

a b,
Caitlin Mulligan, MD , Jeff M. Bronstein, MD, PhD *

KEYWORDS
 Wilson disease  Copper  Movement disorder  Chelation

KEY POINTS
 Wilson disease is a treatable genetic disorder of copper metabolism leading to excess
copper deposition, and it affects function in multiple organ systems, most commonly
the liver and the brain.
 Screening laboratory investigations for Wilson disease should include serum copper,
serum ceruloplasmin, and 24-hour urinary copper. Other tests, such as brain MRI and liver
biopsy, can be helpful, although genetic testing can provide definitive diagnosis.
 Serum copper level is low in Wilson disease.
 Current treatment involves limiting copper intake in the diet, reducing copper absorption
with zinc, chelation therapy to remove copper from the tissues, and treating the symp-
toms. Early recognition of Wilson disease portends a better prognosis for recovery with
therapy.

INTRODUCTION

Wilson disease is one of the few movement disorders in which there are therapies that
modify disease progression. This disease is caused by copper overload primarily in
the liver and brain caused by reduced copper excretion secondary to genetic muta-
tions in the ATP7B gene. Excessive copper leads to a variety of clinical presentations,
including neurologic symptoms, acute or chronic liver failure, and/or psychiatric
manifestations. Because it is a rare autosomal recessive disorder presenting with
such diverse manifestations, there is often a delay in the diagnosis and treatment,
which is unfortunate because it is treatable. This article reviews the clinical presenta-
tion, epidemiology, genetics, pathophysiology, diagnosis, and management of Wilson
disease. Given that there is no universally agreed-on algorithm for treatment, we also
offer an approach to Wilson disease management based on our experience.

a
Department of Neurosciences, University of California, San Diego, 9500 Gilman Drive #0886,
La Jolla, CA 92092, USA; b Department of Neurology, David Geffen School of Medicine at UCLA,
710 Westwood Plaza, Los Angeles, CA 90095, USA
* Corresponding author.
E-mail address: jbronste@mednet.ucla.edu

Neurol Clin - (2020) -–-

https://doi.org/10.1016/j.ncl.2020.01.005 neurologic.theclinics.com
0733-8619/20/ª 2020 Elsevier Inc. All rights reserved.
2 Mulligan & Bronstein

CLINICAL PRESENTATION

Wilson disease was first described in 1912 by Dr Samuel Alexander Kinnier Wilson.1 In
his article published in Brain, he described several cases of progressive neurologic
dysfunction associated with cirrhosis of the liver that ended in death. He proposed
the disease may be called “progressive lenticular degeneration,” although ultimately
it was known as Wilson disease, named after him. Many of the core features of Wilson
disease were described in his initial article, with the most prominent symptoms of
neurologic dysfunction, cirrhosis, and psychiatric features, although it is now known
that there are other systems involved as well. There is great variability in the symptoms
that patients with Wilson disease present with, and for that reason it is sometimes
referred to as the great masquerader.2 It must be kept in mind that there is likely a large
referral bias to many of the case series, so the frequency of neurologic, psychiatric,
and hepatic presentations varies considerably. One study of 282 patients with Wilson
disease in India found that 15% of patients presented with hepatic symptoms only,
69% with neurologic symptoms, 4% with hepatic and neurologic symptoms, and
2% with psychiatric symptoms only.3 Other studies have varied in the estimation,
with hepatologists reporting hepatic presentation in up to 68%.4 Psychiatric problems
are often underappreciated early in the disease.

AGE AT PRESENTATION

Wilson disease generally presents in childhood and young adulthood. The most common
age of presentation is 10 to 20 years,3,5,6 but patients can present before the age of
5 years7,8 and after the age of 70 years.9 In 1 study, 3.8% of 1223 patients with genetically
confirmed Wilson disease became symptomatic at 40 years of age or later.10 Thus,
although most patients present early in life, Wilson disease could still be considered in
the differential diagnosis for patients presenting in middle age. Several studies have sug-
gested that patients with primarily hepatic presentations tend to be younger than those
with neurologic presentations, although both can occur early and late in life.11

NEUROLOGIC SYMPTOMS

The neurologic symptoms of Wilson disease are varied, but most refer to dysfunction
in the extrapyramidal system. Wilson1 originally described the neurologic symptoms
as being purely extrapyramidal, with symptoms of involuntary movements, tremor,
dystonic smile, dysphagia, and dysarthria. This description still holds true, and
neurologic symptoms of Wilson disease include dysarthria, dystonia, gait abnormal-
ities, tremor, parkinsonism, chorea, and (more rarely) seizures. Depending on the
study, there have been a range of reported frequencies of these symptoms. A review
of several independent case series suggests that dysarthria is the most common
neurologic symptom at presentation, followed by gait abnormality/ataxia/cerebellar,
dystonia, parkinsonism, and others as summarized in Table 1.2,3,12,13 The dystonia
in Wilson disease can be focal, segmental, or generalized,14 although the focal dysto-
nia of facial expression causing involuntary smiling is known as risus sardonicus and is
fairly common in Wilson disease.12 Classically, a rubral wing-beating tremor has been
described in Wilson disease, although tremor can also be present at rest, with posture,
or with action.

HEPATIC DYSFUNCTION

There is a spectrum of symptoms from hepatic dysfunction in Wilson disease,

ranging from asymptomatic increase in liver enzyme levels to fulminant liver failure.
 Wilson Disease 3

Table 1
Summary of neurologic symptoms at presentation based on 4 independent case series

Neurologic Manifestations at Onset Patients (%)

Dysarthria 46–97
Gait abnormality/ataxia/cerebellar 28–75
Dystonia 38–69
Parkinsonism 12–58
Postural tremor 55
Dysphagia 50
Chorea/athetosis 6–30
Seizures 6–28
Rest tremor 4
2,3,12,13
Data from Refs.

Typically, early in the disease there is mild increase in transaminitis, which progresses
to chronic active hepatitis, followed by fibrosis and then cirrhosis.15 Cirrhosis may
begin compensated and progress to decompensated cirrhosis with ascites, coagul-
opathy, varices, and encephalopathy. The most common symptoms at presentation
are jaundice, anorexia, and emesis, occurring in 37% to 44%, followed by ascites in
about 23% to 36%, and hepatosplenomegaly in 16% to 29%.15 The presence of
cirrhosis at presentation portends an increased risk of mortality.16 Interestingly, there
seems to be a low risk of hepatocellular carcinoma in patients with Wilson
disease.17,18

PSYCHIATRIC MANIFESTATIONS

Psychiatric manifestations are often the first symptom of Wilson disease, but these
symptoms do not often lead to the diagnosis until neurologic or hepatic symptoms
develop. Wilson described “emotionalism” in 8 of the 12 cases in his initial description
of the disease.1 Psychiatric symptoms can be variable, but affective disorders are more
common than psychosis,19 and common psychiatric features include personality
changes, depression, cognitive changes, and anxiety.20 Personality changes can take
the form of aggression, disinhibition, or obsessiveness. Two large case series suggest
that many patients have psychiatric symptoms at the time of presentation.20,21 One
retrospective case series identified psychiatric manifestations in 64.8% of patients.20
In another study of 195 patients, 51% had psychiatric symptoms at the time of presen-
tation and 20% had seen psychiatrists before the diagnosis of Wilson disease.21 The
delay in diagnosis in patients with primary psychiatric symptoms, estimated to be about
28 months,22 is much greater than other presentations of Wilson disease, which aver-
aged 12 months in a separate study.6 This finding is not surprising because depression
is common in this age group and mild neurologic side effects such as tremor can be side
effects of medications to treat them.

OPHTHALMOLOGIC DYSFUNCTION

The first description of Kayser-Fleischer rings was in 1902 and 1903, before the initial
description of Wilson disease. There was initially debate about its association with Wil-
son disease, but several studies have established that Kayser-Fleischer rings are pre-
sent in 90% to 99% of cases with neurologic symptoms.5,23 However, only a little more
4 Mulligan & Bronstein

than half of patients with hepatic presentations have Kayser-Fleischer rings.23 The
presence of Kayser-Fleischer rings represents copper deposition and is best identified
by a slit lamp examination performed by an experienced ophthalmologist. However, a
recent study also suggests that some patients with Wilson disease with normal slit
lamp examinations were shown to have abnormal anterior segment optical coherence
tomography,24 suggesting that imaging of the corneal membrane may be more sensi-
tive to detecting copper deposition than the traditional slit lamp examination.

OTHER CLINICAL MANIFESTATIONS

Wilson disease can have effects on several other organ systems, including hematolog-
ic (anemia and thrombocytopenia), renal, endocrine, and cardiac systems. Coombs-
negative hemolytic anemia and episodes of jaundice caused by hemolysis can occur
independent of liver disease, although it is rarely the presenting symptom.11 The kid-
neys can be involved in Wilson disease, again independent of liver disease, and there
are reports of renal tubular acidosis and aminoaciduria. Effects on the bone and joints
can present as arthralgias, and some patients have been misdiagnosed with rheuma-
toid arthritis.11 There are various endocrinological effects, including growth and pu-
berty disorders, hypoparathyroidism, dysmenorrhea, and infertility.25 In addition,
patients with Wilson disease have also been found to have mild changes in electrocar-
diography and diastolic dysfunction.26,27

GENETICS AND EPIDEMIOLOGY

Wilson disease is an autosomal recessive condition, although it was not until 1985 that
it was linked to chromosome 13.28 In 1993, 2 separate groups described mutations in
the ATP7B gene in patients with Wilson disease.29,30 Subsequently, there have been
more than 500 mutations in the ATP7B described31; however, there is still much to
learn. Individual gene mutations have not been reliably associated with different pre-
sentations of Wilson disease,32 although there is some evidence that truncating muta-
tions may be associated with earlier onset than missense mutations33 and patients
with frameshift mutations may be more likely to develop neurologic symptoms.34 Inter-
estingly, there are case reports of monozygotic twins who are phenotypically discor-
dant for Wilson disease.35–37 This finding strongly suggests there must be at least
some contribution of environmental and epigenetic factors contributing to Wilson dis-
ease. However, there has been limited success in identifying other genetic loci that
may modify the Wilson disease phenotype, with several genes implicated, including
genes involved in triglyceride metabolism, lipid metabolism, and antioxidant path-
ways.38 Environmental factors thought to make a difference include gender,32
iron,39 and dietary factors.39
Wilson disease is a rare disorder, although the prevalence has varied depending on
the study, with the most widely cited prevalence of 1 in 30,000.40 More recent studies
in China41 and France42 suggest a lower prevalence of 1 in 56,000 to 1 in 66,000,
respectively. The frequency of individuals carrying pathogenic mutations is higher
than expected. This finding has been confirmed in multiple populations in France,43
the United Kingdom,44 and China.45 In addition, 1 study showed a higher than ex-
pected frequency of Wilson disease in the offspring of patients with Wilson disease.46
Thus, there is some debate about the true prevalence of Wilson disease and whether
there are patients with Wilson disease that have not been diagnosed and are not being
picked up in the epidemiologic studies. In addition, there may be incomplete pene-
trance, and there is at least 1 case in the literature of a patient carrying 2 mutations
 Wilson Disease 5

in the ATP7B gene presenting with hepatitis but without any evidence of alteration in
copper metabolism.47

PATHOPHYSIOLOGY

Copper is a cofactor in many enzymes and is necessary for normal metabolism. One
example is cytochrome c oxidase, which is involved in the final step of the electron
transport chain and uses copper as a cofactor to perform this function. People
consume approximately 1 mg/d of copper in their diets and excrete 90% of the un-
used copper in bile, which is eventually eliminated in stool and the remainder in the
urine. In Wilson disease, patients cannot excrete copper efficiently in the bile and
therefore it accumulates in the liver and brain.
Wilson disease is caused by a defect in the ATP7B gene, which encodes a P-type
adenosine triphosphatase. The function of this protein is to load copper onto apoc-
eruloplasmin in the Golgi apparatus to become ceruloplasmin in hepatocytes.
Normally, the ceruloplasmin would then be excreted into bile with copper bound
to it, functioning as the major pathway to remove excess copper from the body. In
Wilson disease, the malfunction of the ATP7B protein leads to an inability to load
copper onto ceruloplasmin in the Golgi apparatus, and therefore an inability to
appropriately excrete copper into bile (Fig. 1). As a result, copper builds up in the he-
patocyte and subsequently leaks into the blood. Copper exists in 2 pools in the
blood: ceruloplasmin bound (85%–95%) and non–ceruloplasmin bound or free cop-
per (5%–15%), which is loosely bound to albumin and available for uptake by cells or
to participate in metabolism.48 Apoceruloplamin is ceruloplasmin unbound to copper
and is quickly degraded in the blood stream, leading to a low serum ceruloplasmin
levels in Wilson disease. Because most serum copper is normally bound to cerulo-
plasmin and ceruloplasmin levels are low in Wilson disease, total serum copper level
is low in the disease and free unbound copper level is increased. Copper toxicity is
thought to be mediated by oxidative stress and creation of free radicals, mediated by
free copper participating in metabolic reactions.5 Ultimately, it is this copper toxicity

Fig. 1. In normal metabolism (left), copper (gold dots) enters hepatocyte cytoplasm via the
copper transporter (CTR) and into the Golgi apparatus (brown) by an ATPase (blue) coded by
the ATP7B gene. Copper is then transported via vesicles and secreted into bile in the free
state or into the plasma protein bound (ceruloplasmin). A defective Wilson ATPase (red) re-
sults in impaired copper transport into the Golgi and vesicles and decreased secretion into
bile. Intracellular copper level increases, leading to hepatocyte cell death and copper
leakage into the plasma. A greater portion of apoceruloplasmin remains unbound to copper
in Wilson disease and is secreted into the plasma. It is then rapidly degraded, which results
in lower ceruloplasmin level.
6 Mulligan & Bronstein

that leads to the hepatic and neurologic dysfunction. The pathophysiology of the
skeletal and hematologic problems seen in some patients with Wilson is poorly
understood.

DIAGNOSIS
Laboratory Tests
Several laboratory investigations are helpful in establishing the diagnosis of Wilson
disease, and these are summarized here, followed by the diagnostic criteria.
Ceruloplasmin
Serum ceruloplasmin level is low in most patients with Wilson disease. It is known that
other conditions may also cause ceruloplasmin level to be low, including individuals
heterozygous for ATP7B mutations, as well as other disease affecting the loss of pro-
tein (eg, nephrotic system) or synthesis of protein (eg, end-stage liver disease, malnu-
trition). In addition, increases in ceruloplasmin level may occur as an acute phase
reactant49 and with other hormonal conditions such as pregnancy and while taking
oral contraceptives.50 Studies have suggested that the sensitivity of low ceruloplasmin
level (<20 mg/dL) for Wilson disease range from 80% to 99%,3,5,51 although the spec-
ificity is lower. A large study of serum ceruloplasmin in China found that the sensitivity
of ceruloplasmin level less than 20 mg/dL for Wilson disease was 99% and the spec-
ificity was 80.9%, but less than 15 mg/dL had a lower sensitivity of 95% and higher
specificity of 95%.51 In addition, with patients with hepatic presentations, low cerulo-
plasmin level may be less predictive of Wilson disease, and 1 study found that low
ceruloplasmin level in the setting of liver disease had a positive predictive value of
5.9%.52 Thus, the other factors, such as clinical presentation and other laboratory
tests, are needed to make the diagnosis of Wilson disease.
Serum copper and free copper
Serum copper level is a measure of the total copper in the serum, regardless of
whether it is bound to protein (ceruloplasmin or albumin) or unbound (free). Because
ceruloplasmin level is low in Wilson disease, and copper is mostly carried by cerulo-
plasmin in the serum, the total serum copper level is typically low in patients with Wil-
son disease despite the disease being caused by copper overload. The serum copper
is not indicative or useful on its own, but free copper is a marker of disease. Although
some specialized laboratory tests are able to measure free copper level directly, this is
not widely available and thus free copper level is typically calculated by subtracting
ceruloplasmin level (mg/dL) times 3 from total serum copper level (mg/dL) to estimate
the level of non–ceruloplasmin-bound copper. Normal free copper level is less than
10 mg/dL, and in Wilson disease it is typically higher than this. However, because
free copper level is an indirect value, it can be negative and is not always reliable.
Urinary copper
The urinary excretion of copper is an important measure of copper excretion. As
mentioned earlier, normally copper is excreted mainly through bile; in Wilson disease,
the biliary copper excretion is reduced and there is increased urinary copper excretion
as a result. For accurate interpretation of the urinary copper, patients must take home
a copper-free container to collect urine for a full 24 hours. This requirement can be
challenging in pediatric patients and, if urine is not collected correctly, there can be
a falsely low value. In Wilson disease, 24-hour urinary copper level is typically more
than 100 mg in 24 hours in adults. If urinary copper level is mildly increased and there
is a question of Wilson disease, urinary copper can be measured before and after
penicillamine to evaluate whether urinary copper level increases after penicillamine
 Wilson Disease 7

(500 mg every 12 hours), which would be expected if there is an excess of copper

stored in tissues.

Additional blood tests

Liver function tests, including aspartate aminotransferase (AST), alanine amino-
transferase (ALT), gamma-glutamyl transferase, bilirubin, alkaline phosphatase,
and prothrombin time, can be helpful measures of liver function. A complete blood
count can show Coombs-negative hemolytic anemia, thrombocytopenia, and so
forth.

MRI Brain
For those patients with neurologic symptoms, MRI of the brain can be helpful to estab-
lish any stereotypical findings consistent with Wilson disease, as well as to rule out
other causes of neurologic symptoms. Although the so-called face of the giant panda
sign, which consists of increased T2 signal in the midbrain, has been thought to be
pathognomonic for Wilson disease, there are multiple MRI changes that can occur
in Wilson disease. An excellent retrospective study of 100 patients with early-onset
extrapyramidal disorders compared them with 56 patients with Wilson and found
that the face of the giant panda sign was present in only 14% of patients with Wilson
disease and 0% of patients with other pediatric extrapyramidal disorders, and thus it is
fairly specific but not sensitive.53 Other MRI findings include signal changes in the
basal ganglia, thalami, pons, and white matter, as well as atrophy.53 MRI lesions are
reversible in most patients with treatment, and were correlated with clinical improve-
ment in 1 study, although patients with extensive changes were less likely to
improve.54

Liver Biopsy
Liver biopsy is sometimes obtained as part of the diagnostic work-up for Wilson dis-
ease, especially in patients with hepatic presentations. Total hepatic copper is the
most useful diagnostic from the liver biopsy, and has a sensitivity estimated to be
83% when liver copper level is greater than 250 mg/g.55 Stains such as rhodanine
detect the abnormal presence of lysosomal copper but are not sensitive for the diag-
nosis.56 False-negatives caused by sampling error remain a significant problem in us-
ing liver biopsies for the diagnosis of Wilson disease.55,57

Genetic Testing
Genetic testing of the ATP7B gene is considered the gold standard for diagnosis of
Wilson disease. However, because of the variability in genetic mutations that have
been described, looking for common polymorphisms misses possible pathogenic mu-
tations, and direct sequencing of the entire gene is recommended.58

DIAGNOSTIC CRITERIA

In 2003, the Leipzig criteria for the diagnosis of Wilson disease were put forth by the
European Association for the Study of the Liver (EASL).50 These criteria consider both
clinical and laboratory data to establish the diagnosis and are summarized in Table 2.
The criteria use a combination of clinical examination and laboratory findings, with a
diagnosis established after achieving at least 4 points. These criteria are used in
research settings; however, they also can be helpful for practicing physicians who
are trying to establish the diagnosis of Wilson disease, especially in settings in which
genetic testing is difficult to obtain.
8 Mulligan & Bronstein

Table 2
Diagnostic criteria for Wilson disease according to Leipzig criteria

Clinical or Laboratory Finding Points

Kayser-Fleischer Rings Present 2
Absent 0
Neurologic Symptoms or MRI Findings Severe 2
Mild 1
Absent 0
Serum Ceruloplasmin Level (g/L) <0.1 2
0.1–0.2 1
Normal (>0.2) 0
24-h Urinary Copper >2 upper limit of normal 2
1–2 upper limit of normal 1
Normal 0
Normal, but >5 upper limit 2
of normal after D-penicillamine
Coombs-negative Hemolytic Anemia Present 1
Absent 0
Total Liver Copper Level (mmol/g) >5 upper limit of normal (>4) 2
Increased (0.8–4) 1
Normal (<0.8) 1
Rhodanine-positive granules present 1
Genetic Mutation Present on both chromosomes 4
Present on 1 chromosome 1
Absent 0
Total Score Diagnosis established 4
Diagnosis possible, more tests needed 3
Diagnosis unlikely 2 or less

Adapted from Liver EA for the S of the. EASL Clinical Practice Guidelines: Wilson’s disease. J Hep-
atol. 2012;56(3):671-685; with permission.

MANAGEMENT

The overall goal of therapy is to establish normal copper homeostasis by balancing

copper intake and excretion. In patients with copper overload, the goal of therapy is
net negative copper balance, which can be achieved by increasing excretion via
chelation therapy, as well as reducing copper absorption with zinc and reducing di-
etary intake. Once proper balance is established, maintenance can often be
achieved using zinc and low-copper diet alone, but it sometimes requires ongoing
chelation.

MEDICATIONS

Multiple medications are approved for the treatment of Wilson disease, with 1
medication currently under study in a phase III clinical trial for Wilson disease. The
medications vary in mechanism, side effects, and potency, which is summarized in
Table 3. D-Penicillamine and trientine both work as chelating agents by binding with
copper, which is then eliminated in the urine and therefore promotes copper excretion.
In contrast, zinc salts inhibit the absorption of copper from the diet by inducing expres-
sion of the endogenous copper chelator metallothionine in the gut and liver. Bis-
choline-tetrathiomolybdate is currently under study, but has a novel mechanism of
action and it works by complexing free copper to albumin, sequestering free copper
 Table 3
Medications for Wilson disease

Drug Mechanism Dosing Side Effects Potency

D-Penicillamine Chelates copper and Titrated up to 1 g/d, Fever, rash, anemia, bone Very effective at attaining negative
promotes urinary e divided into 2–4 doses marrow suppression, copper balance, 5–10 mg/d in early
xcretion Must be taken 30 min lymphadenopathy, lupuslike therapy60
before meals or 2 h syndrome, worsening neurologic
after meals symptoms
Trientine Chelates copper and Titrated up to 1 g/d, Proteinuria, bone marrow suppression, Less effective attaining negative copper
promotes urinary divided into 2–4 doses autoimmune reactions, worsening balance, 2–3 mg/d in early therapy60
excretion Must be taken 30 min neurologic symptoms
before meals or 2 h
after meals
Zinc salts Induces metallothionine 50 mg TID Gastrointestinal upset Weak, <1 mg/d60
in gastrointestinal Must be taken
epithelium and inhibits at least 1 h
copper absorption before or after meals
Bis-choline- Complexes free copper 15 mg/d Transaminitis, bone marrow suppression To be determined
tetrathiomolybdate with albumin
(under phase III
clinical trial)

Abbreviation: TID, 3 times a day.

Wilson Disease
9
10 Mulligan & Bronstein

from participating in metabolic reactions.48 A similar drug, ammonium tetrathiomolyb-

date, was previously studied with beneficial anticopper effects, but it was too unstable
for practical use.59 The drugs also differ in effectiveness in reducing total body copper
level, with D-penicillamine being the most potent at copper efflux, and zinc salts being
least potent.60 A large retrospective study of patients receiving trientine and D-penicil-
lamine supports the 2 drugs having similar effectiveness, but with increased side ef-
fects in the D-penicillamine group.61 However, the quality of studies comparing the
efficacy of anticopper medications has been limited to smaller, unrandomized trials.62
A meta-analyses does support the superiority of D-penicillamine to placebo, but there
was mixed evidence comparing zinc with D-penicillamine.62 When chelation therapy is
indicated, the authors generally prefer starting with trientine rather than D-penicilla-
mine because it has fewer side effects.
The potential for neurologic worsening is another important consideration in select-
ing a treatment of Wilson disease. The frequency of worsening neurologic symptoms
early after starting chelation therapy has been described in many studies, occurring
between less than 10% and 50% of patients.61,63–65 It remains unclear whether there
is a difference in the frequency of neurologic worsening between chelating agents.62
Increase of serum free copper level precedes neurologic worsening in patients treated
with trientine, 48 and it has been suggested that chelation increases the free copper,
which is available to create free radicals and contributes to further damage. For this
reason, chelation therapy should be started at low dose if the patient has neurologic
symptoms and needs to be closely monitored. If neurologic decline does occur, the
dose of the chelator should be reduced or even stopped and zinc therapy should
be used. This situation can often be a conundrum because the goal is to reduce cop-
per levels in brain and the liver as fast as possible to limit permanent damage, but
chelating too fast with traditional chelators can cause additional damage. Thus, the
novel mechanism of tetrathiomolybdate as complexing free copper is attractive theo-
retically, and the recent phase II trial supports the low rate of neurologic worsening,59
although larger studies are needed and underway.

LIVER TRANSPLANT

Liver transplant is an effective therapy for patients with liver disease. Transplant of a
normally functioning liver into a patient with Wilson disease essentially restores normal
copper excretion, as well as normal liver function. However, liver transplant is a com-
plex procedure requiring lifelong immunosuppression and is typically reserved for pa-
tients with acute liver failure or decompensated cirrhosis.56,66

DIET

Following a low-copper diet is a commonsense lifestyle modification that should work

to reduce the overall copper load to the body. In general, it is recommended that pa-
tients should try to consume less than 1 mg/d of total copper, which is not difficult to
achieve by avoiding the highest copper content foods (ie, shellfish and liver) and eating
other foods rich in copper (ie, chocolate, nuts, dried fruits, beans, and mushrooms) in
moderation. Water can contain high concentrations of copper if it comes from copper
piping. Most water filters do not remove copper, although running the water to flush
the pipes greatly reduces the levels. Purified or distilled water contain almost no cop-
per. Avoid using copper cooking pots as well.
There is little direct evidence of the effectiveness of a low-copper diet in treating Wil-
son disease,67 but it is logical to reduce the intake within reason.
 Wilson Disease 11

SYMPTOM MANAGEMENT

Although much of the focus is on anticopper therapies, symptom management is

also an important component of medical therapy. Hepatic complications such as
esophageal varices and ascites are treated symptomatically similar to advanced
liver disease of other causes. For neurologic symptoms, medications to treat parkin-
sonism, such as carbidopa/levodopa, can be tried but are not necessarily effec-
tive.12 Treatments for dystonia can be tried, including anticholinergic medications
such as trihexiphenidyl or local muscle relaxants with botulinum toxin injections
for focal dystonia. Deep brain stimulation targeting ventral intermediate nucleus of
thalamus for tremor and the globus pallidus interna for dystonia have been tried,
but with variable success in a limited number of patients.68 In addition, taking a multi-
disciplinary approach and involving speech therapy for dysarthria and dysphagia, as
well as physical therapy and occupational therapy, may be helpful as well. Psychiat-
ric manifestations can be managed with serotonin reuptake inhibitors or neurolep-
tics, although there is some evidence that patients with Wilson disease are more
sensitive to neuroleptics.19

PREVENTION

Once a patient is diagnosed with Wilson disease, siblings at risk should be screened.
Because Wilson disease is an autosomal recessive disease, siblings of affected
patients are at a 25% risk of having the disease. Siblings, whether or not they are
symptomatic, should be screened with liver function tests, neurologic examination,
ophthalmologic examination, and functional tests of copper metabolism (cerulo-
plasmin, 24-hour urinary copper), or genetic testing. If the specific genetic mutations
are known, siblings can be tested for those polymorphisms or with haplotype analysis
of polymorphisms in genes flanking ATP7B.58 In addition, there have been efforts to
develop population screening tests for newborns to detect presymptomatic Wilson
disease. Although initial studies of ceruloplasmin were unsuccessful, a new test quan-
tifying the amount of ATP7B protein in serum is promising for an appropriate screening
tool.69

PROGNOSIS

Before the development of medical therapies, Wilson disease was inevitably a fatal
disease.1 Early diagnosis is important and has been shown to be associated with
reduced mortality and need for liver transplant,16,50,70 and the life expectancy is
estimated to be near that of the general population.71 In addition, health-related
quality of life in treated patients with Wilson disease is similar to that of the general
population.72 However, compliance is an important factor for prognosis,71 and
there are reports of death in patients who were previously well controlled on med-
ications who became noncompliant.73 With regard to reversibility of symptoms,
most evidence suggests that both neurologic and hepatic symptoms
improve with appropriate therapy in most patients,5,16,74,75 although dystonia
may be the least likely of the neurologic symptoms to respond to treatment.75 Psy-
chiatric symptoms are also expected to improve with anticopper treatment,
although there may a plateau in response after 2 years of treatment.20 Despite a
favorable response to treatment in most patients, there are also reports of
patients who have died despite early diagnosis and treatment, and there is a
concept that some patients do not respond conventionally to copper-reducing
agents.70,76
12 Mulligan & Bronstein

APPROACH TO MANAGEMENT

There is no consensus on treating patients with Wilson disease, but there is some gen-
eral agreement on overall approach. The authors would like to share our treatment
approach at Wilson disease center of excellence.
When starting anticopper therapy on a newly diagnosed patient, the goal of therapy is
to achieve a net negative copper balance. However, the urgency of copper level reduction
should be evaluated depending on the clinical scenario. When symptoms are already pre-
sent, there is a more urgent need to reduce copper level for the best chance of symptom
reversal and to prevent further disease progression, and thus the more potent chelating
medications are indicated. In asymptomatic patients, there is less urgency to reduce cop-
per levels and it may be possible to use zinc and a low-copper diet alone.
For asymptomatic patients, the authors typically start with zinc 50 mg 3 times per day
on an empty stomach along with a low-copper diet. The authors monitor neurologic
symptoms and liver function tests as well as urinary copper excretion every 3 months.
If the patient develops symptoms at any time, we add a chelating agent. If the urinary cop-
per level increases from baseline, we also consider adding a chelating agent at that time.
For symptomatic patients, we typically use trientine if available through the patient
health insurance because of the preferable side effect profile, but D-penicillamine is an
appropriate alternative if trientine is not available. For both medications, we typically
start with a dosage of 250 mg/d on an empty stomach and increase by 250-mg incre-
ments every 7 to 14 days to a maximum of 1000 to 1500 mg daily divided into 2 to 3
doses. For children and adults who weigh less than 45 kg (100 lb), we recommend
starting with 250 mg daily with a maximum total daily dose of 20 mg/kg in 2 or 3
divided doses. We monitor the neurologic status closely and reduce the dose if there
is evidence of decline at any point. Liver function tests, complete blood count with
platelets, serum copper and ceruloplasmin, and 24-hour urine copper are monitored
approximately every 3 months during chelation. We find the 24-hour urine copper to
be more accurate than spot serum free copper levels (indirectly measured) for moni-
toring copper status. Urine copper level increases once chelation is initiated but even-
tually come down as copper stores are depleted. Once the 24-hour urine copper level
decreases to 100-200 mg/d, which often can take 6 to 12 months, the patient enters
the maintenance phase of therapy.
In the maintenance phase of therapy, the goal is to maintain a net even copper bal-
ance. After chelation therapy, many patients are able to achieve this with zinc and low-
copper diet alone, although some patients remain on low-dose chelation therapy. As
discussed earlier, we use urinary copper as a marker of copper status, which is moni-
tored every 6 months in the maintenance phase along with serum copper, cerulo-
plasmin, blood counts, and liver function tests. An increase in the urinary copper to
more than 100 mg/d suggests an increase in systemic copper stores, which reflects
noncompliance or insufficient anticopper therapy. This condition should be addressed
by stressing compliance, adding back chelating drug, or increasing the dose of
chelator therapy until urinary copper level decreases to less than 100 mg/d again.
Because of the chronic nature of Wilson disease and the potential for worsening
with noncompliance, we continue to monitor laboratory tests every 6 months indefi-
nitely for patients with Wilson.

DISCLOSURE

C. Mulligan: none. J.M. Bronstein: site principal investigator of the phase 2 and 3 trials
of tetrathiomolybdate in Wilson disease run by Alexion and has received funds only to
complete these studies.
 Wilson Disease 13

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