Handbook of Clinical Neurology, Vol.

100 (3rd series)

Hyperkinetic Movement Disorders
W.J. Weiner and E. Tolosa, Editors
# 2011 Elsevier B.V. All rights reserved

Chapter 49

Wilson’s disease
RONALD F. PFEIFFER *
Department of Neurology, University of Tennessee Health Science Center, Memphis, TN, USA

HISTORICAL ASPECTS corneal rings, and cirrhosis (Fleischer, 1912), which

In what might be viewed as an inspiration to all doctoral
candidates, Wilson’s disease (WD) derives its name
from the 1911 doctoral thesis of S. A. Kinnear Wilson,
subsequently published in Brain (Wilson, 1912), in which
he described in over 200 pages of exhaustive detail the
clinical and pathological features of 12 patients (four
whom he had followed personally and 8 similar cases
from the literature) with the disease process he called
progressive lenticular degeneration, but which today is
known by his name. Wilson considered progressive len-
ticular degeneration to be a “familial nervous disease
associated with cirrhosis of the liver.” Other descriptions
of what was likely the same disease process had been
published earlier (Frerichs, 1860; Westphal, 1883;
Gowers, 1888; Ormerod, 1890; Homen, 1892; Strümpell,
1898), but it was Wilson whose perspicacity permitted
recognition that at least some of these disparate descrip-
tions likely were examples of the same distinct disease
process. The descriptions of Westphal and Strümpell
bear particular note in that they carried the diagnostic
label of pseudosclerosis and were generally considered
a separate disease entity from progressive lenticular
degeneration until 1920, when Spielmeyer concluded
that the pathology of the two entities was identical. Sub-
sequently, the name hepatolenticular degeneration was
first applied to WD (Hall, 1921).
Ten years prior to Wilson’s report, Kayser in 1902
and Fleischer in 1903 described the rings of corneal
pigmentation now associated with WD. In 1912, the
same year in which Wilson’s work was published,
Fleischer expanded upon his earlier report and
described what he considered a previously unrecog-
nized, but pseudosclerosis-related, disease character-
ized by tremor, mental disturbance, pigmented
clearly fits the description of WD.
In describing what was then considered a case of
pseudosclerosis, Rumpel (1913) was the first to identify
excess copper in the liver in WD. However, it was not
until 1948, when Mandelbrote and colleagues (1948)
noted increased urinary excretion of copper and Cum-
ings (1948) documented copper deposition in both liver
and brain, that copper deposition was recognized as the
source of pathology in WD. Four years later, cerulo-
plasmin deficiency was documented in WD (Bearn
and Kunkel, 1952; Scheinberg and Gitlin, 1952). It took
another two decades before impaired biliary excretion
of copper was identified as the avenue of copper accu-
mulation within the liver (Frommer, 1974). Recent dec-
ades have witnessed the unfolding of the genetic basis
of WD.
GENETICS
In the title of his thesis and initial publications, Wilson
characterized WD as familial but he did not describe it
as hereditary. It was 9 years later that WD was identified
as having a genetic basis, although the initial conclusion
that the defect was transmitted by two different genes
proved inaccurate (Hall, 1921). It was subsequently iden-
tified as an autosomal-recessive disorder (Bearn, 1960).
In 1985, chromosome 13 was proposed as the location
of the mutation causing WD (Frydman et al., 1985). This
prompted further intensive investigation that led in 1993
to the near-simultaneous localization and identification
of the gene by several groups of investigators (Bull
et al., 1993; Petrukhin et al., 1993; Yamaguchi et al.,
1993). The gene, ultimately christened ATP7B, was
mapped to 13q14.3 and found to cover a region of
approximately 80 kb and contain 21 exons that encode

*Correspondence to: Ronald F. Pfeiffer, MD, Department of Neurology, University of Tennessee Health Science Center,
855 Monroe Avenue, Memphis, TN 38163, USA. Tel: (901) 448-5209, Fax: (901) 448-7440, E-mail: rpfeiffer@utmem.edu
682 R.F. PFEIFFER
a transcript of approximately 7.5 kb (Bull et al., 1993;
Petrukhin et al., 1993, 1994; Yamaguchi et al., 1993;
Terada et al., 1998).
The protein encoded by the gene, also labeled
ATP7B, is a copper-transporting ATPase that binds 6
copper molecules (DiDonato et al., 1997; Lutsenko
et al., 1997). ATP7B protein is expressed primarily in
the liver and kidneys and within the liver appears to
perform a dual function, depending on the copper sta-
tus within the liver. ATP7B typically resides within the
trans-Golgi network in hepatocytes where, under nor-
mal conditions, it functions to transport copper across
organelle membranes, thus enabling the incorporation
of copper into apoceruloplasmin to form ceruloplas-
min. However, when copper becomes elevated within
the liver, ATP7B is redistributed to cytoplasmic vesi-
cles and assumes a different function, which entails
transporting copper across the hepatocyte apical mem-
brane into the bile canaliculus, from whence the excess
copper is excreted (Forbes and Cox, 2000; La Fontaine
et al., 2001). In WD, mutation at the ATP7B locus
results in defective ATP7B protein that cannot trans-
port copper for incorporation into ceruloplasmin, with
consequent abnormally low serum ceruloplasmin
levels, and cannot assist in the biliary excretion of
excess copper, which inevitably leads to a gradual but
relentless rise in copper levels within the liver and
eventually in other tissues.
ATP7B is also expressed in stomach and small intes-
tine (Weiss et al., 2008). Its function in the intestine is
uncertain, but it could conceivably play a role in main-
taining copper homeostasis within enterocytes by either
sequestering copper within the enterocytes or facilitating
its apical excretion. In either case, it might modulate
intestinal copper absorption.
Although WD is an autosomal-recessive disorder,
it is not the result of a single consistent genetic muta-
tion. An ever-increasing array of mutations has been
identified and most individuals with WD are com-
pound heterozygotes with two different mutations –
one from each parent – combining to produce the
defective ATP7B protein. Currently the number of
mutations identified has ballooned to over 400
(Schmidt, 2009) and undoubtedly more will be discov-
ered. Although missense mutations have been the most
frequently identified mutation type, deletions, inser-
tions, nonsense, and splice-site mutations all occur (Lou-
dianos et al., 2002). Within the USA and in individuals
of northern, central, and eastern European origin, the
H1069Q mutation in exon 14 occurs most frequently
(Tanzi et al., 1993; Thomas et al., 1995; Brewer, 2001;
Ferenci, 2006). Within these European populations,
approximately 50–80% of WD patients carry at least
one allele with this mutation, with an allele frequency
ranging between 30 and 70% (Ferenci, 2006). A differ-
ent picture emerges in other parts of Europe and in
other areas of the world. In Spain, the M645R missense
mutation in exon 6 is common (Margarit et al., 2005),
while in Saudi Arabia a deletion mutation in exon 21
(4193delC) appears to be predominant (Majumdar
et al., 2003), and in Korea the R778L missense mutation
in exon 8 is most frequent, with an allele frequency of
approximately 37% (Yoo, 2002). This mutational
heterogeneity has made it very difficult to perform
genetic testing for screening and diagnostic purposes
in routine clinical practice, although limited mutation
analysis can be employed in populations where certain
mutations have been identified as the predominant
source of WD. It is very probable, however, that techni-
cal advances will make genetic analysis a practical and
routine component of the evaluation of suspected WD
in the not too distant future.
Recognition that multiple mutations may be respon-
sible for WD prompted speculation that differences in
the location and type of mutations within the ATP7B
gene might account for the immense variability in the
clinical presentation of individuals with WD (Thomas
et al., 1995). However, such genotype–phenotype corre-
lation has not been evident in subsequent studies and
individuals with identical mutations may differ widely
in both age of symptom onset and clinical manifesta-
tions (Shah et al., 1997; Folhoffer et al., 2007). The fact
that even monozygotic twins with WD, despite their
identical genetic makeup, may display markedly
different clinical manifestations strongly suggests that
factors beyond simple genetic makeup play a role in
the development and progression of WD (Czlonkowska
et al., 2009).
EPIDEMIOLOGY
WD is rare. This has rendered accurate assessment of
incidence and prevalence rates problematic. The most
widely published figure for prevalence has been 30 cases
per million (Scheinberg and Sternlieb, 1984), although
increased awareness and more accurate diagnosis of
WD in recent years suggest that actual prevalence might
be higher (Mak and Lam, 2008). Prevalence rates also
demonstrate considerable geographic variability. In
Japan, a prevalence rate of 33–68 per million has been
reported (Meenakshi-Sundaram et al., 2008), compared
with a prevalence rate of 12–29 per million in Europe.
A worldwide incidence rate between 1 per 30 000 and
100 000 live births is often quoted (Thomas et al.,
1995; Brewer, 2001; Yoo, 2002; Majumdar et al., 2003;
Margarit et al., 2005), while for the USA an incidence
rate of 1 per 55 000 live births has been calculated
(Olivarez et al., 2001).
 WILSON’S DISEASE 683
PATHOPHYSIOLOGY ceruloplasmin deficiency in WD is secondary to its
reduced formation because of the failure within the liver
Copper is both essential and potentially toxic for cellu-
of defective ATP7B to transport copper for incorpora-
lar functioning. As an essential trace element, it is a
tion into apoceruloplasmin to form ceruloplasmin. The
component of a variety of enzyme systems that include
ceruloplasmin gene itself is on chromosome 3 and is
cytochrome c oxidase, dopamine beta-hydroxylase,
normal in WD (Yang et al., 1986).
superoxide dismutase, tyrosinase, and others (Peña et al.,
Ceruloplasmin deficiency may also be present in other
1999). When allowed to accumulate in excess it readily
conditions. Aceruloplasminemia, an autosomal-recessive
participates in reactions that result in the generation
disorder due to mutations in the ceruloplasmin gene with
of highly reactive oxygen species, which can produce
consequent failure to form ceruloplasmin (McNeill et al.,
devastating cellular damage (Peña et al., 1999). Precise
2008), is characterized by dramatic iron deposition in liver,
regulatory mechanisms have evolved to police the
pancreas, and brain, but only modest hepatic copper accu-
uptake, transport, delivery, and storage of copper
mulation (Morita et al., 1995; Hellman and Gitlin, 2002).
within the body.
Chronic liver disease, such as hepatitis C infection, can
Daily dietary copper intake is typically in the range
also result in ceruloplasmin deficiency (Jones et al.,
of 2–5 mg/day (Roberts and Sarkar, 2008; Roberts
2000). Menkes’ disease is yet another condition in which
and Schilsky, 2008). Intestinal absorption by entero-
ceruloplasmin deficiency is present. There are also situa-
cytes is accomplished through the high-affinity copper
tions where transient ceruloplasmin deficiency can
transport protein, Ctr1, and copper is escorted within
develop, as in the setting of deficient protein and calorie
the enterocyte to its intended destination by one of
intake, diseases producing impaired protein absorption,
several chaperones, such as CCS, COX17, or Atox1
or protein-wasting conditions (Gibbs and Walshe, 1979).
(Prohaska, 2008). Atox1 delivers copper to the protein
Although increased urinary excretion of copper is a
responsible for secretion of copper from the entero-
hallmark of WD, it is clear that the primary route of
cyte, ATP7A (Menkes’ protein), then exports copper
copper excretion from the body under normal conditions
from the enterocyte (Lönnerdal, 2008). ATP7B is also
is via the gastrointestinal tract, more specifically via
present within the enterocyte, but its role is uncertain.
biliary excretion (van Berge Henegouwen et al., 1977).
Within the liver, copper stored in hepatocytes is
Copper is also routinely excreted in saliva and gastric
primarily bound to metal-binding proteins such as
juice, but the copper excreted from these sources is
metallothionein or incorporated into several cuproen-
reabsorbed more distally in the gastrointestinal tract
zymes (Luza and Speisky, 1996). For transport to other
and then re-excreted by the biliary route (Owen, 1964;
parts of the body, copper is bound primarily to albu-
O’Reilly et al., 1971). In WD, mutation at the ATP7B gene
min, ceruloplasmin, or transcuprein. Approximately
produces defective ATP7B protein that is not capable of
90% of this transport is performed by ceruloplasmin,
carrying out its transport functions within the hepatocyte.
with most of the remainder by albumin. Ceruloplasmin
Thus, copper is not delivered for ceruloplasmin forma-
was first isolated in 1948, the same year in which cop-
tion, nor is it transported into the bile canaliculus for
per deposition was first noted to be present in WD
excretion. The defect in biliary excretion of copper
(Holmberg and Laurell, 1948), but it was not until 4
results in slow, but relentless accumulation of copper
years later that ceruloplasmin deficiency was docu-
within the liver. Eventually, however, the ability of the
mented to be present in WD (Bearn and Kunkel,
liver to store the accumulating copper is exceeded and,
1952; Scheinberg and Gitlin, 1952). Ceruloplasmin is
like a flooding river breaching its levee, unbound copper
an a2-glycoprotein that binds and transports 6 copper
escapes from the liver into the blood stream and is
molecules. There are actually multiple forms of cerulo-
carried to other tissues where it is deposited and begins
plasmin, with molecular weights ranging from 115 000
to accumulate. The dramatic increased urinary copper
to 200 000 (Sato et al., 1990). Although ceruloplasmin
excretion so characteristic of WD represents a heroic,
is deficient in patients with WD, deficiency is not
but inadequate, effort by the body to compensate for
obligatory and, in fact, ceruloplasmin levels are normal
the impaired biliary excretion, and the relentless accu-
or only slightly reduced in 5–15% of individuals with
mulation of copper in liver, brain, and other tissues
WD (Gibbs and Walshe, 1979; Scheinberg and Sternlieb,
ultimately results in tissue damage.
1984; Brewer, 2001). To complicate the issue further,
10–20% of heterozygotes, who remain clinically normal
CLINICAL FEATURES
and do not develop symptoms of WD, may actually
have reduced levels of ceruloplasmin (Gibbs and Walshe, The escape of copper from the liver results in its depo-
1979). It is important to remember that WD is not the sition in multiple organs throughout the body and this,
consequence of ceruloplasmin deficiency. Rather, in turn, sets the stage for the multisystemic clinical
684 R.F. PFEIFFER
involvement that is so characteristic of WD. The diverse
array and variability of the clinical features of WD
present a particular challenge for diagnosis. Depending
on the mode of clinical presentation or the medical prac-
tice milieu, the individual with WD may arrive in or be
referred to the office of a family practitioner, internist,
gastroenterologist, neurologist, psychiatrist, or other
specialist for evaluation, and all need to be tuned to
the possibility of WD. Although the liver is where the
process of WD begins, hepatic dysfunction is not neces-
sarily its initial clinical manifestation.
To aid in the diagnosis and assessment of patients
with WD, several scoring systems and scales have
been devised and tested. One scoring system was
published by a group of experts following the 8th
International Meeting on Wilson and Menkes Dis-
eases (Ferenci et al., 2003). Aggarwal and colleagues
(2009) proposed and tested a global assessment
scale (GAS for WD) specifically intended for use in
routine clinical practice to allow more objective
assessment of patients with WD. The Unified Wilson’s
Disease Rating Scale (UWDRS) has also been
developed and tested (Czlonkowska et al., 2007;
Leinweber et al., 2008).
Hepatic manifestations
Not surprisingly, hepatic dysfunction is usually con-
sidered the most frequent mode of initial clinical pre-
sentation of WD. Approximately 40–50% of patients
with WD experience hepatic symptoms as their initial
manifestation (Walshe, 1962; Brewer, 2001). Some geo-
graphic variability exists in that the percentage of WD
patients presenting with hepatic dysfunction as the ini-
tial manifestation is even higher in Japanese and Chinese
populations (Chu and Hung, 1993). The reason for this
is unclear. Individuals in whom hepatic dysfunction
accounts for their initial clinical symptoms tend to pres-
ent at an earlier age (average 11.4–15.5 years) than those
with a neurologic or psychiatric presentation (Strickland
and Leu, 1975; Walshe, 1976; Merle et al., 2007). Onset
of symptoms before age 6 is rare, but has been
reported, and elevation of liver enzymes has been docu-
mented in children with asymptomatic WD as early as
age 2 (Mak and Lam, 2008). In adults, the oldest initial
onset of WD in the form of hepatic dysfunction was
age 74 (Czlonkowska et al., 2008). In the experience of
one group of investigators, 17% of patients were over
age 40 at the time of diagnosis (Gow et al., 2000). Indi-
viduals presenting with hepatic symptoms tend to be
diagnosed more quickly than those presenting with neu-
rologic or psychiatric features. In one study, persons
with hepatic presentation were diagnosed within an
average of 14.4 months after symptom onset, compared
with a delay of 44.4 months for those with neuropsy-
chiatric presentations (Merle et al., 2007).
Hepatic involvement in WD may emerge in one of
several guises. The most frequent mode of presentation
is slowly progressive hepatic failure with cirrhosis,
ascites, esophageal varices, and splenomegaly. As the
progressive liver failure deepens, hepatic encephalopa-
thy may emerge. With this presentation, there are no
characteristics that would specifically identify the liver
failure as being due to WD. In its early stages, indivi-
duals with this mode of presentation may simply display
asymptomatic enlargement of liver and spleen in con-
junction with abnormalities of liver function tests.
A picture of acute transient hepatitis, similar in
many aspects to that seen with viral-induced hepatitis,
develops in approximately 25% of cases. Individuals
may develop jaundice, loss of appetite, nausea, fatigue,
and muscle and joint aching. A family history of WD, or
even a family history of unexplained hepatic, neuro-
logic, or psychiatric disease, should alert treating physi-
cians to the possibility of WD as the source of the
hepatic dysfunction. The concomitant presence of hemo-
lytic anemia also may serve as an important signal to
consider the possibility of WD in an individual presenting
with acute hepatitis (Brewer, 2001). In conjunction
with this, unconjugated (indirect) bilirubin may also be
elevated.
Yet another potential mode of hepatic presentation
for WD, evident in 10–30% of individuals, is a clinical
picture very similar to autoimmune (chronic active)
hepatitis (Sternlieb and Scheinberg, 1972; Scott et al.,
1978). Both the clinical and the laboratory features of
autoimmune hepatitis may be present in these WD
patients (Schilsky et al., 1991) and an initial response
to steroids or other immunologic therapy may occur
(Milkiewicz et al., 2000). The diagnosis of WD in this
presentation may also be obscured by the fact that
serum ceruloplasmin, as an acute-phase reactant, may
rise to within the low normal range in some individuals
(Sternlieb and Scheinberg, 1972; Brewer, 2001).
The most feared, but also the least common, mode
of hepatic presentation of WD is acute fulminant
hepatic failure, which occurs in approximately 5% of
individuals (Lech et al., 2007). This presentation is
characterized by the development of rapidly developing
liver failure accompanied by coagulopathy, encephalop-
athy with cerebral edema, renal failure, and metabolic
derangements that emerge over a period of 1–4 weeks
(Gill and Sterling, 2001; Stravitz and Kramer, 2009).
Although the presentation may be one of acute
liver failure, in individuals with WD the pathologic
picture is indicative of acute liver failure superimposed
on chronic, though previously unrecognized, hepatic
injury with cirrhosis (Korman et al., 2008). However,
 WILSON’S
fulminant hepatic failure without evidence of cirrhosis
has been reported in WD (Enomoto et al., 1989). Two-
thirds of patients in whom WD begins as fulminant
hepatic failure are female; most are younger than age
30 and often they are teenagers (Schilsky et al., 1994).
Diagnosis of WD in fulminant hepatic failure can be
exceedingly difficult. Liver biopsy is often impossible
to perform because of the presence of coagulopathy
and 24-hour urine copper determination may be diffi-
cult to obtain because of development of renal failure
in the form of hepatorenal syndrome (Markiewicz-
Kijewska et al., 2008). Ceruloplasmin levels also
become unreliable (Korman et al., 2008). However,
some laboratory features can be useful in identifying
WD in these circumstances. Acute liver failure results
in a massive release of copper from the liver, with con-
sequent marked elevation of serum copper levels, often
to levels greater than 200 mg/dL (Roberts and Schilsky,
2008). Severe Coombs-negative hemolytic anemia, most
probably due to intravascular hemolysis precipitated by
the massive release of copper into the blood stream,
may also be present (Roche-Sicot and Benhamou,
1977). The pattern of liver enzyme abnormalities in ful-
minant hepatic failure may also provide clues to the
diagnosis of WD. In contrast to the pattern present in
viral hepatitis, alkaline phosphatase and aminotransfer-
ase levels are often disproportionately low, while total
bilirubin may be disproportionately elevated due to
hemolysis (Hoshino et al., 1995; Kenngott and Bilzer,
1998; Brewer, 2001). Korman and colleagues (2008) sug-
gested that the combination of an alkaline phosphatase:
total bilirubin ratio of less than 4 and an aspartate amino-
transferase:alanine aminotransferase ratio of greater
than 2.2 in this setting is highly suggestive of WD,
especially if hemoglobin is also reduced. Glycosuria,
hypophosphatemia, and hypouricemia may also develop
due to renal dysfunction (Lech et al., 2007). The progno-
sis for individuals with WD who present with fulminant
hepatic failure is very grim; mortality is virtually 100%
without liver transplantation (Shafer and Shaw, 1989;
Rela et al., 1993; Schilsky et al., 1994).
In light of the clinical variability that WD-induced
hepatic dysfunction can display, it has been recom-
mended that WD should be considered in the differen-
tial diagnosis of any individual under age 50 with
unexplained liver disease (Brewer, 2001).
Neurologic manifestations
Neurological dysfunction is the second most frequent
initial clinical manifestation of WD, although esti-
mates of this range from 40 to 60% and, in the
experience of some, neurological presentation is more
frequent than hepatic (Walshe, 1962; Brewer, 2001).
DISEASE 685
When neurological symptoms are the initial clinical
feature of WD, the average age of symptom onset is
later than when the initial presentation is hepatic. The
average age of onset for hepatic presentations of WD
is 11.4–15.5 years, compared with 18.9–20.2 years for
neurological presentations (Strickland and Leu, 1975;
Merle et al., 2007). Onset of neurological dysfunction
as the presenting feature of WD has been reported as
early as age 6 (Strickland and Leu, 1975) and as late
as age 72 (Ala et al., 2005).
A broad array of neurological features may develop in
the setting of WD. Features of basal ganglia dysfunction
– both hyperkinetic and hypokinetic – may appear, as may
manifestations of cerebellar and other central nervous
system involvement.
Tremor is the most frequent initial manifestation of
neurological involvement in WD, ushering in neurologi-
cal dysfunction in approximately 50% of individuals
(Walshe, 1986). In one report describing 119 persons with
WD, tremor was present at the time of diagnosis in 60%
(Machado et al., 2006). Tremor may be present at rest, or
it may be postural or kinetic in character. It typically is
asymmetric and, when a limb is involved, may be either
predominantly proximal or distal in location. The tremor
of WD may be rapid and fine or it may be slower and
coarser. Proximal, coarse tremors involving the arms
may assume a “wing-beating” appearance that is often
associated with WD. If the cervical muscles are involved,
head titubation may be evident. Tremor may appear in
isolation or in conjunction with other signs of neuro-
logical dysfunction. Isolated tongue tremor has been
described in WD (Topaloglu et al., 1990; Topaloglu and
Renda, 1992). Because of the diverse appearances that
tremor may assume in WD, it is important to consider
WD in the differential diagnosis of any tremor that
develops in young persons, even when family history is
negative (Nicholl et al., 2001).
Dystonia is also very common in neurological WD
(Fig. 49.1). In fact, in the experience of some investiga-
tors it is even more frequent than tremor, present at
the time of diagnosis in 69% of WD patients (Machado
et al., 2006). In the experience of others, dystonia is
present in 37–42% of patients (Huang and Chu, 1992;
Svetel et al., 2001a; Soltanzadeh et al., 2007). Cervical
dystonia has been reported as the initial manifestation
of WD (Basir et al., 2009). “Risus sardonicus,” the fixed
facial grimace/smile that is most closely associated with
tetanus but may also occur in WD, is produced by
dystonia of the facial muscles. Status dystonicus trig-
gered by zinc therapy may also occur in WD (Teive
et al., 2005).
Chorea occurs relatively infrequently in WD
(Starosta-Rubinstein et al., 1987). It was present at the
time of diagnosis in 16% of 119 WD patients (Machado
686 R.F. PFEIFFER
Fig. 49.1. Dystonia of hands, jaw, and periorbital muscles in
an individual with advanced Wilson’s disease
et al., 2006) but was the initial neurological abnormality
in only one of 307 WD patients (Prashanth et al., 2004).
Athetosis is also described in patients with WD and
some investigators find it to be among the more com-
mon neurological features of WD (da Costa Mdo
et al., 2009). Athetosis was present at the time of diag-
nosis in 14% of patients (Machado et al., 2006).
Parkinsonism, characterized by rigidity and bradyki-
nesia, is frequently present in individuals with WD
(Barbosa et al., 1993; Mueller et al., 2006; Leiros da
Costa et al., 2009). In one report, 45% of 136 WD
patients presenting with neurological dysfunction were
parkinsonian (Walshe and Yealland, 1992). Rest tremor
is an infrequent presenting neurological feature of
WD, but may occur in approximately 5% of patients
(Machado et al., 2006). Mueller and colleagues (2006)
demonstrated that extrapyramidal dysfunction in WD
may be accompanied by olfactory impairment, just
as in PD.
Although unusual, myoclonus has been observed in
WD (Barbosa et al., 2007). White-matter changes, involv-
ing temporal, parietal, and frontal lobes may be noted in
conjunction with generalized myoclonus. Truncal myoc-
lonus associated with priapism and seminal ejaculation
has been described (Nair and Pillai, 1990).
Cerebellar dysfunction develops in 25–50% of indi-
viduals with WD (Walshe and Yealland, 1992; Jha et al.,
1998). It may take the form of ataxia, dysarthria,
kinetic (intention) tremor, or incoordination. It is often
difficult to decide whether symptoms such as incoordi-
nation and dysarthria are due to basal ganglia dysfunc-
tion, cerebellar dysfunction, or a combination of both.
Dysarthria eventually develops in the majority of
individuals with WD. In one study it was present in
85% of patients (Oder et al., 1991) and in another was
the most frequent neurological feature at the time of
diagnosis, evident in 91% of individuals (Machado
et al., 2006). Several patterns of dysarthria have been
described. Hypokinetic dysarthria is characterized by
difficulty initiating speech, reduced speech volume,
reduced phonation and intonation, inadequate tongue
movement, and imprecise articulation, along with a
tendency for speech to accelerate as a sentence proceeds
(Hoogenraad, 1996). Dystonia involving the tongue and
facial muscles can also produce profound dysarthria,
even to the point of anarthria. This has been labeled
hyperkinetic dysarthria (Hoogenraad, 1996). Another
type of dysarthria observed in WD appears to be cere-
bellar or brainstem in origin and is characterized by
scanning, explosive speech. Although each of these pat-
terns of dysarthria may appear in its pure form, it is far
more typical for the dysarthria in WD to consist of a
mixture of features.
Dysphagia may develop during the course of WD
and may be present in up to 50% of individuals at the
time of diagnosis (Machado et al., 2006). Difficulty at
all levels involved with swallowing – oral, pharyngeal,
and esophageal – may be present (Haggstrom and
Hirschowitz, 1980; Gulyas and Salazar-Grueso, 1988; da
Silva Júnior et al., 2008). Impaired swallowing may be
evident on objective testing even when patients are not
subjectively experiencing dysphagia (da Silva Júnior
et al., 2008). An association between dysphagia and a
particular genetic mutation (3402delC) has been noted
but the significance of this is uncertain (Machado et al.,
2008a).
Some investigators have described a “Wilson’s facies”
that is characterized by a variable combination of open
mouth, pseudoptosis, decreased eye contact, drooping
angle of the mouth, and delayed or absent changes in
facial expression that collectively produce a dull, expres-
sionless face (Aggarwal et al., 2009). Decreased facial
expression has been described in approximately 41% of
persons with WD at the time of diagnosis (Huang and
Chu, 1992). An unusual laugh, in which most of the
sound is generated during inspiration, has also been
described in WD (Cartwright, 1978).
Gait abnormalities are another common neurologic
feature of WD (Soltanzadeh et al., 2007). Some distur-
bance of gait has been reported in 45–75% of WD
patients at the time of diagnosis (Huang and Chu,
1992; Machado et al., 2006). The gait impairment in
WD ranges from parkinsonian, with small shuffling
steps and difficulty initiating gait, to cerebellar, with
a wide-based and unsteady appearance (Brewer, 2001).
Autonomic dysfunction is an overlooked phenome-
non in WD. Some investigators have noted its presence
in 26–38% of persons with WD (Bhattacharya et al.,
2002: Meenakshi-Sundaram et al., 2002). Some
report that parasympathetic function is impaired more
 WILSON’S
frequently than sympathetic (Soni et al., 2009), while
others maintain that sympathetic function is predomi-
nantly affected (Chu et al., 1997). Autonomic dysfunc-
tion may be the presenting feature of WD (Kumar,
2005).
A variety of other neurological features may
develop in WD, but with much less frequency. Seizures
are reported in 4–6% of patients (Dening et al., 1988;
Huang and Chu, 1992; Machado et al., 2006).
Seizures are said to be more frequent in WD in Asia
(Chu and Hung, 1993). Status epilepticus is rare, but
does occur (Knight et al., 2009). An unusual pattern
of “circling” seizures, presumably frontal-lobe in ori-
gin, has been described (Saka et al., 1999). The combi-
nation of seizures and psychiatric disturbances may
indicate the presence of frontal-lobe white-matter
lesions (Huang and Chu, 1995). Headache may be the
presenting feature of WD in 10% of patients
(Scheinberg and Sternlieb, 1984). A variety of sleep dis-
orders, including hypersomnia (Firneisz et al., 2000)
and altered rapid-eye-movement sleep function (Portala
et al., 2002), have been reported in WD. A pseudobulbar
syndrome may occur (Dobyns et al., 1979; Hoogenraad,
1996).
Neither upper motor neuron signs (weakness, spastic-
ity, hyperreflexia, Babinski responses) nor lower motor
neuron signs (hyporeflexia) are typically seen in WD.
Sensory loss and sphincter dysfunction are unusual.
Psychiatric manifestations
In his initial description of WD, Wilson described
behavioral or “psychical” changes in eight of his 12
patients (Shanmugiah et al., 2008). Psychiatric symptoms
have been reported to be either the presenting feature
of WD or evident prior to diagnosis in approximately
15–20% of individuals (Dening and Berrios, 1989; Mak
and Lam, 2008; Shanmugiah et al., 2008). However,
some reports indicate the presence of psychiatric symp-
toms at the time of diagnosis in a considerably higher
percentage of patients. Akil and colleagues (1991) noted
psychiatric symptoms to be present in 65% of 42 patients
with WD at the time of initial presentation, and further-
more mentioned that the psychiatric difficulties were
severe enough to warrant treatment in almost 50% of
the symptomatic patients before the diagnosis of WD
was made. Most individuals with WD experience psychi-
atric dysfunction at some point during the course of their
illness, often in conjunction with neurological abnormal-
ities. Unfortunately, delays in diagnosis seem especially
likely to occur when psychiatric symptoms are the pre-
senting feature of WD, and such delays have a negative
effect on treatment outcome (Walshe and Yealland,
1992; Srinivas et al., 2008).
DISEASE 687
Psychiatric dysfunction in WD may appear in a variety
of guises, running the gamut from subtle personality
changes to frank psychosis (Lauterbach et al., 1998).
Changes in personality and behavior that have been
reported in WD include emotional lability, irritability,
impulsiveness, childishness, reduced anger threshold,
aggressiveness, recklessness, and disinhibition (Walshe,
1975; Dening and Berrios, 1989; Akil et al., 1991; Oder
et al., 1991; Akil and Brewer, 1995). Shanmugiah and collea-
gues (2008) labeled excessive talkativeness, aggressive
behavior, abusiveness, and loss of interest in surroundings
as key symptoms of psychiatric dysfunction in WD.
Mood disorders may develop in WD. Major depres-
sion develops in 27% of patients (Oder et al., 1991) and
mild depression in others (Lauterbach et al., 1998).
Suicidal behavior has been described in 4–16% of WD
patients (Oder et al., 1991; Akil and Brewer, 1995). Mania
may be the initial manifestation of WD (Machado et al.,
2008b).
Acute psychosis may also be the presenting feature of
WD and, if the diagnosis of WD is not considered, the
subsequent emergence of neurological dysfunction may
be misinterpreted as neuroleptic-induced toxicity (Saint-
Laurent, 1992; Jukić et al., 2006). Circadian rhythm
abnormalities have been reported in WD patients with
psychiatric dysfunction, suggesting the presence of hypo-
thalamic dysfunction (Matarazzo, 2002). Disturbances
such as alterations in blood pressure, temperature, and
pulse rate may be helpful in pointing toward the presence
of WD in patients with a psychiatric presentation. Psy-
chosis in WD may be characterized by paranoid ideation,
delusional thinking, and hallucinations; catatonia has also
been reported (Scheinberg et al., 1968; Dening, 1985;
Brewer and Yuzbasiyan-Gurkan, 1992; Davis and Borde,
1993). Antisocial or criminal behavior has been reported
in WD (Kaul and McMahon, 1993), as has sexual preoc-
cupation and disinhibition (Scheinberg and Sternlieb,
1984; Akil et al., 1991). A somewhat unusual aspect of
psychiatric dysfunction that has been described is the
development of severe psychosis in conjunction with
recovery of motor function following initiation of copper
chelation therapy in individuals who were severely
impaired and mute prior to treatment. This has been
christened “emergent psychosis” and attributed to
improved motor function unveiling previously masked
psychosis (Aggarwal et al., 2009). Subsequent improve-
ment in the psychosis with continued chelation therapy
is consistent with this attribution.
Dementia may develop in patients with advanced
disease, but is uncommon. Mild cognitive impairment is
frequently present, but develops in less than 25% of
patients (Lauterbach et al., 1998). Abnormalities of fron-
tal executive ability, visuospatial processing, and some
aspects of memory have all been described and formal
688 R.F. PFEIFFER
neuropsychiatric testing may demonstrate a variety of
abnormalities (Rathbun, 1996; Portala et al., 2000,
2001a, b; Seniow et al., 2002). It has been suggested that
the appearance of mild cognitive impairment in WD is
simply subclinical hepatic encephalopathy (Tarter et al.,
1987) but others disagree (Akil and Brewer, 1995).
Ophthalmologic manifestations
The ophthalmological hallmark of WD is the formation
of Kayser–Fleischer rings (KFRs) within the cornea
(Fig. 49.2). Although excess copper is actually depos-
ited throughout the cornea when it escapes from the
liver, it becomes visible only in Descemet’s membrane
because of the formation of sulfur–copper complexes
there (Wiebers et al., 1977; Johnson and Campbell,
1982). KFRs do not impair or obstruct vision. They
are virtually always bilateral, but unilateral KFRs have
been described, possibly as a consequence of reduced
intraocular pressure in the eye without the ring (Madden
et al., 1985; Innes et al., 1986). KFRs range in color from
gold to brown to green, but more unusual coloration –
ruby red, bright green, ultramarine blue – has been
described (Suvarna, 2008). Because of their color, KFRs
often can be identified quite easily in individuals with
blue eyes, but can be difficult or impossible to visualize
in brown-eyed persons without the benefit of slit-lamp
examination. KFRs first appear in the superior aspect
of the cornea, followed by the inferior aspect; the
medial and lateral portions of the ring then subsequently
fill in (Innes et al., 1986). Because of this pattern of ring
evolution, it is important to lift the eyelid during clinical
examination for KFRs, so that incomplete ring forma-
tion is not overlooked (Sussman and Scheinberg, 1969).
Formation of the ring begins in the periphery of the
cornea and spreads centrally toward the pupil. However,
in some individuals a clear area between the pigment
and the corneoscleral junction may be present (Tauber
and Steinert, 1993).
Fig. 49.2. Kayser–Fleischer ring in an individual with Wilson’s
disease. (Courtesy of Dr. William Weiner.)
KFRs are virtually always present in individuals
with WD who have developed neurologic or psychiatric
symptoms, but they may not yet have formed in persons
who present with only hepatic involvement. They may
also be absent in presymptomatic individuals. In a review
of 282 cases of WD, Taly and colleagues (2007) noted
KFRs to be present in 100% of patients with neurological
dysfunction, compared with 86% in persons who dis-
played only hepatic involvement and 59% in presympto-
matic individuals. Others report that KFRs are evident
at the time of diagnosis in only 44–62% of patients
presenting with hepatic dysfunction and that they are
typically absent in children presenting with hepatic
dysfunction (Roberts and Schilsky, 2008). The absence
of KFRs in the face of neurological involvement in WD
has been reported (Ross et al., 1985; Willeit and Kiechl,
1991) but this must be extremely rare.
While the presence of KFRs is very suggestive of a
diagnosis of WD, it is not pathognomonic. In fact, pig-
mented corneal rings indistinguishable from KFRs have
been described in a number of conditions characterized
by hepatic dysfunction. Examples include primary biliary
cirrhosis (Fleming et al., 1977; Tauber and Steinert, 1993),
autoimmune hepatitis (Frommer et al., 1977), possible
partial biliary atresia (Frommer et al., 1977), cryptogenic
cirrhosis (Frommer et al., 1977; Rimola et al., 1978), and
chronic cholestatic jaundice (Kaplinsky et al., 1980). Pro-
cesses other than liver disease can also result in corneal
copper deposition and ring formation, although the loca-
tion of the rings may not match that seen in WD. Estro-
gen-based oral contraceptives can elevate serum copper
levels and this may result in copper deposition and ring
formation within the cornea in Descemet’s membrane,
but within the mid-periphery rather than the outer edges
of the cornea (Garmizo and Frauens, 2008). Corneal
copper deposition may also develop in conditions such
as chronic lymphocytic leukemia (Aldave et al., 2006),
multiple myeloma (Goodman et al., 1967; Lewis et al.,
1995), and pulmonary carcinoma (Martin et al., 1983).
In these instances, the copper deposition is due to the
combination of markedly elevated gamma-globulin and
copper, and the copper deposition is central, rather than
peripheral, within the cornea. In further contrast to
WD, the central corneal copper deposition in these cases
may produce impairment of vision (Aldave et al., 2006).
Localized ocular processes may also stain the cornea
and mimic KFRs. Copper sulfate-containing ophthalmic
solutions, utilized to treat trachoma prior to the intro-
duction of antibiotics, were reported to stain the cornea
(Stephenson, 1902), as may intraocular copper-containing
foreign bodies (Wiebers et al., 1977).
Corneal staining unrelated to copper deposition
may occur. Arcus senilis, a common condition due to
lipid deposits within the corneal periphery, is easily
 WILSON’S DISEASE
distinguishable from KFRs because of its whitish-gray
coloration. However, if an individual also has hyper-
carotenemia from excessive carotenoid ingestion, the
arcus senilis may take on a yellowish hue and be mis-
taken for KFRs (Giorgio et al., 1964). Fleischer’s ring,
seen in keratoconus as a result of iron deposition in
basal epithelial cells, develops as a greenish or brown-
ish ring in the peripheral cornea that may be mistaken
for KFRs (Suvarna, 2008). Corneal heme staining
following cataract removal may also transiently mimic
KFRs (Frommer et al., 1977).
The sunflower cataract, first described by Siemerling
and Oloff (1922), is a much less frequent ocular mani-
festation of WD. Sunflower cataracts are found in only
2–17% of individuals with untreated WD (Wiebers et al.,
1977; Huo et al., 2008). They result from the anterior
capsular deposition of copper (Herron, 1976) and have
a sunflower or sunburst-like appearance, consisting of
a central powder-like disc with radiating petal-like spokes
(Cairns et al., 1969; Wiebers et al., 1977). Slit-lamp exami-
nation is generally required to visualize sunflower catar-
acts. They do not interfere with vision.
A variety of other ophthalmologic abnormalities
have been described in WD. Abnormalities of oculo-
motor function are frequently present. In one study
of 34 patients, electro-oculographic recording demon-
strated abnormal vertical smooth pursuit in 85% and
impaired horizontal smooth pursuit in 41% of the sub-
jects, along with vertical optokinetic nystagmus in 41%
(Ingster-Moati et al., 2007). Other investigators have
reported impairment of both smooth-pursuit move-
ments and voluntary saccades, with preservation of
reflexive saccades (Leśniak et al., 2008). Still other
ophthalmological abnormalities have been described in
individuals with WD, including white retinal spot for-
mation (Pillat, 1933), night blindness (Walsh and Hoyt,
1969), optic neuropathy with rapidly progressive vision
loss (Gow et al., 2001), difficulty with gaze fixation
(Lennox and Jones, 1989), eyelid-opening apraxia
(Keane, 1988), and oculogyric crises (Lee et al., 1999).
However, whether these isolated reports reflect rare
ophthalmologic abnormalities of WD or are simply
coincidental findings is uncertain.
Musculoskeletal manifestations
Bone and joint involvement is quite common in WD,
especially in Asia (Chu and Hung, 1993). This higher
frequency of musculoskeletal manifestations has been
noted in Chinese (Xu et al., 1981), Japanese (Saito,
1987), and Indian (Dastur et al., 1968) populations.
Radiographic evidence of osteoporosis has been noted
in up to 88% of individuals with WD (Golding and
Walshe, 1977; Canelas et al., 1978). The development
689
of osteoporosis may already be evident early in the
course of the disease. Osteoporosis was already
present in 67.7% of 31 children with newly diagnosed
WD in one study and the overall prevalence of
decreased bone mineralization was 90.3% (Selimoglu
et al., 2008). Increased bone resorption may be respon-
sible (Hegedus et al., 1992). Osteomalacia, rickets, and
localized bone demineralization all may occur (Yarze
et al., 1992). Spontaneous fractures have been reported
(Selimoglu et al., 2008).
Joint involvement is frequent in WD. Both joint
hypermobility and joint stiffness and pain, suggestive
of premature osteoarthritis, have been described (Feller
and Schumacher, 1972; Golding and Walshe, 1977;
Canelas et al., 1978; Bálint and Szebenyi, 2000). Calci-
fications within and around joints may develop (Yarze
et al., 1992) and radiologic evidence of vertebral
column abnormalities is evident in 20–33% of patients
(Mindelzun et al., 1970; Golding and Walshe, 1977).
The arthropathy in WD may result from copper and
iron deposition within joints, with consequent free
radical-induced tissue destruction producing synovial
and cartilage damage (Kramer et al., 1993).
Hematologic manifestations
Coombs-negative hemolytic anemia, often but not
always in conjunction with hepatic dysfunction, may be
the initial manifestation of WD in 10–15% of cases
(McIntyre et al., 1967; Sternlieb, 1984; Yarze et al., 1992;
Roberts and Schilsky, 2003). The hemolytic anemia may
be mild and transient but also may be severe and herald
the development of fulminant hepatic failure (Yarze
et al., 1992; Lee et al., 1998; Brewer, 2001). The combina-
tion of unexplained, Coombs-negative hemolytic anemia
and liver disease, especially when occurring in a young
person, should always prompt evaluation for possible
WD (Brewer, 2001). Thrombocytopenia may develop in
individuals with WD, either in conjunction with hemolytic
anemia or as an isolated abnormality (Donfrid et al.,
1998; Prella et al., 2001).
Renal manifestations
Renal involvement may occur in WD. Although unusual,
it may be the presenting feature in some individuals.
In one study, it was the initial symptom in 8% of 85
children (Zhuang et al., 2008). Renal impairment was
evident in 40% of the 85 children at some point during
the course of the disease and in 29% of the 85 it could
not be attributed to penicillamine (Zhuang et al., 2008).
Renal tubular dysfunction, induced by excessive urinary
copper, can result in hypercalciuria and hyperphospha-
turia with consequent nephrocalcinosis (Wiebers et al.,
690 R.F. PFEIFFER
1979; Hoppe et al., 1993). Hematuria, proteinuria, amino-
aciduria, and glucosuria all may occur (Strickland and
Leu, 1975; Sözeri et al., 1997; Zhuang et al., 2008).
Myocardial manifestations
Myocardial involvement in WD is not widely recognized,
but is surprisingly common. Factor and colleagues (1982)
reviewed autopsy findings in nine individuals who had
suffered from WD and discovered evidence of cardiac
hypertrophy in 5 (56%). Fibrosis, intramyocardial small-
vessel sclerosis, and focal inflammation were evident in
each instance and consistent with the presence of a
cardiomyopathy. Two of the five individuals had suf-
fered sudden death, presumably due to cardiac arrhyth-
mia. In a prospective study of 53 WD patients, Kuan
(1987) documented electrocardiographic abnormalities
in 34%. Two cardiac deaths were recorded in this group
of individuals, one from ventricular fibrillation and one
from dilated cardiomyopathy. In another study, 30% of
50 WD patients demonstrated at least one abnormality on
electrocardiographic examination (Meenakshi-Sundaram
et al., 2004). A broad array of abnormalities was evident
in both studies. Myocardial damage in WD is presumably
due to copper deposition within the heart (Azevedo et al.,
1978; Kaduk et al., 1980).
Other manifestations
Autonomic dysfunction, most often asymptomatic and
evident only upon electrophysiological testing, has been
noted in almost 40% of persons with WD, predomi-
nantly among individuals with neurological involvement
(Meenakshi-Sundaram et al., 2002). Both sympathetic
and parasympathetic systems are affected. Reduced
sweat volume may also be present in untreated WD
(Schaefer et al., 2008).
Skin changes may occur in WD. Wilson described
hyperpigmentation of the legs and a dark complexion
in his initial treatise (Wilson, 1912). Anterior lower-leg
hyperpigmentation appears to be especially prone to
develop in Chinese patients with WD (Chu and Hung,
1993), where it was evident in 60% of patients in one
study (Leu et al., 1970). Such hyperpigmentation may
be mistaken for Addison’s disease. Bluish discoloration
of the lunulae of the nails (Bearn and McKusick, 1958)
and acanthosis nigricans (Ezzo et al., 1957) have been
reported in WD.
Menstrual irregularity (Scheinberg and Sternlieb,
1965; Lau et al., 1990; Erkan et al., 2002), delayed
puberty (Sternlieb and Scheinberg, 1985), and gyneco-
mastia (Yarze et al., 1992) have all been described in
patients with WD, as have glucose intolerance and
parathyroid insufficiency (Yarze et al., 1992).
DIAGNOSTIC EVALUATION OF WD
Appropriate treatment of WD is dependent upon diag-
nosis. The protean nature of the clinical manifestations
of WD can pose an incredible challenge for the physician
charged with the responsibility not only to diagnose WD,
but also to do so expeditiously before permanent damage
to liver, brain, or other systems occurs. A single, simple,
failsafe diagnostic test for WD would be ideal and, with
the rapid advances currently unfolding in genetic testing
capability, may become reality in the future (Wilson
et al., 2009). It does not exist today, however, and accu-
rate diagnosis is still dependent upon the judicious and
expeditious employment of a constellation of diagnostic
studies. It is incumbent upon the clinician constantly to
bear in mind the possibility of WD when confronted with
any individual, especially a young person, with unex-
plained hepatic, neurologic (especially if there is basal
ganglia or cerebellar involvement), or psychiatric dys-
function, or even involvement of other systems in the
body that can be affected by WD. McIntyre (1993) has
aptly stated that “the most important single factor in
early diagnosis [of WD] is suspicion of the disease.”
Genetic testing
The identification of over 400 different mutations in
individuals with WD (Schmidt, 2009), with more certain
to be identified, makes genetic testing impractical as a
screening tool. It is important to recognize that negative
genetic testing does not exclude a diagnosis of WD.
One or both causative mutations are not found in up
to 20% of individuals with unequivocal WD who
undergo genetic testing, probably because the responsi-
ble mutations are in the promotor region of the ATP7B
gene, which is not analyzed during current routine
genetic analysis (Houwen, 2008). However, targeted
genetic diagnostic screening programs may be useful
in some regional populations where specific mutations
are known to account for the vast majority of cases
(Caca et al., 2001; Folhoffer et al., 2007; Kumar et al.,
2007), and genetic screening of relatives of WD patients
in whom the responsible mutations have been identified
is certainly advisable (Schmidt, 2009).
Liver biopsy
Determination of hepatic copper content via liver biopsy
is the single most sensitive and accurate test for the
diagnosis of WD. Hepatic copper content will be signi-
ficantly elevated in the vast majority of individuals
with WD, even those who are clinically asymptomatic.
Hepatic copper elevation in WD is typically quite
striking, with levels greater than 250 mg/g dry tissue,
compared to normal values of 15–55 mg/g. However, it
 WILSON’S
must be noted that lower than expected hepatic copper
levels may be found if the biopsy is performed just as
copper is being mobilized from the liver and released
into the general circulation. In this situation, hepatic
copper will still be elevated, but the elevation may be
only in the range of 100 mg/g rather than the expected
250 mg/g or greater (Sternlieb et al., 1987). In one study,
3.5% of patients diagnosed with WD had hepatic copper
levels below 50 mg/g and in 13% the hepatic copper level
was between 50 and 250 mg/g (Ferenci et al., 2005).
Some investigators have suggested that a hepatic copper
content of less than 75 mg/g dry tissue virtually excludes
the diagnosis of WD, while levels between 75 and 250
mg/g are indeterminate (Ferenci et al., 2005; Mak and
Lam, 2008). The possibility that nonuniform distribution
of copper within the liver might lead to a sampling error
has led some investigators to emphasize the need for an
adequately sized biopsy sample of 1–2 cm (Snow, 1995),
while others suggest that false-negative biopsy results
are simply due to inadequate laboratory technique
(Brewer, 2001).
Elevations of hepatic copper content may also be
present in other conditions characterized by hepatic
dysfunction, particularly obstructive liver diseases.
Hepatic copper may be increased in primary biliary
cirrhosis, biliary atresia, extrahepatic biliary obstruc-
tion, primary sclerosing cholangitis, intrahepatic chole-
stasis of childhood, Indian childhood cirrhosis, and
autoimmune hepatitis (Smallwood et al., 1968; LaRusso
et al., 1976; Evans et al., 1978; Benson, 1979; Tanner
et al., 1979).
Liver biopsy does entail a small, but definite, risk of
complication, especially in patients with severe liver
disease and consequent coagulopathy. It should not be
used as a first-line screening procedure in every indi-
vidual suspected of having WD. Instead, it should be
reserved for those instances where simpler and safer
measures have not provided a definitive diagnosis.
In patients with neurological or psychiatric dysfunc-
tion, liver biopsy is generally unnecessary since other
tests will provide the diagnosis. It is, however, usually
required in individuals presenting with hepatic
dysfunction.
Slit-lamp examination
The visualization of KFRs is invaluable in the diagnosis
of WD. However, in many individuals with WD, espe-
cially those with brown eyes, KFRs are not readily visible
on routine examination. Slit-lamp examination by a
neuro-ophthalmologist or experienced ophthalmologist
is a vital part of the diagnostic evaluation for suspected
WD, particularly in persons with neurological or psychi-
atric dysfunction.
DISEASE 691
While the absence of KFRs does not exclude a diag-
nosis of WD and their presence does not provide
unequivocal diagnostic proof of WD, the identification
of KFRs in an individual is very strong evidence in
support of such a diagnosis. It has been stated that
the absence of KFRs in a patient with neurologic symp-
toms or signs excludes the diagnosis of WD (Scheinberg
and Sternlieb, 1984). However, a number of cases where
KFRs were absent in individuals with WD and neurolog-
ical dysfunction have been reported (Ross et al., 1985;
Oder et al., 1991; Willeit and Kiechl, 1991; Vidaud
et al., 1996). Individuals with only hepatic dysfunction
may not display KFRs because copper accumulation
may not yet have exceeded the liver’s capacity to store
copper. Presymptomatic WD persons often do not have
KFRs for the same reason.
Ceruloplasmin
Serum ceruloplasmin determination is a simple and
readily available screening study for suspected WD, but
the potential for both false-negative and false-positive
values means that it cannot be relied upon as the sole
screening study in individuals in whom a diagnosis of
WD is being considered.
Ceruloplasmin may be normal or only slightly lower
than normal in 5–15% of persons with WD, resulting in
a false-negative value (Scheinberg and Sternlieb, 1984;
Brewer, 2001). Ceruloplasmin levels may also
transiently rise into the normal range in persons with
WD in certain circumstances. Since ceruloplasmin is
an acute-phase reactant, it may increase during preg-
nancy, while taking birth control pills, during estrogen
or steroid administration, during infections, or in the
setting of various inflammatory processes, including
hepatitis (Gibbs and Walshe, 1979; Brewer, 2001).
Individuals with WD may transiently have normal or
near-normal ceruloplasmin levels if they develop these
conditions (Sternlieb and Scheinberg, 1972). However,
a ceruloplasmin level above 30 mg/dL is believed by
some investigators virtually to exclude the possibility
of WD (Yarze et al., 1992); others consider the level
to be 40 mg/dL (Snow, 1995).
False-positive levels may also be reported in a number
of situations in which ceruloplasmin levels are low but
WD is not present. As many as 10–20% of heterozygotes
for WD, who have one defective copy of the ATP7B gene
but neither develop symptomatic WD nor require any
treatment, may have subnormal ceruloplasmin levels
(Scheinberg and Sternlieb, 1984; Brewer, 2001; Roberts
and Schilsky, 2008). Ceruloplasmin levels may also be
reduced, either transiently or continuously, in a number
of other conditions, including chronic liver disease of
any cause.
692 R.F. PFEIFFER
24-Hour urinary copper excretion
Urinary copper levels in patients with symptomatic WD
typically are greater than 100 mg/day. However, just as
with ceruloplasmin levels, an elevated 24-hour urinary
copper level is not necessarily present in all patients
with WD, nor is an elevation pathognomonic for WD.
If an individual with WD has not yet developed
symptoms, the 24-hour urinary copper excretion may
be within the normal range because the ability of the
liver to store accumulating copper has not yet been
exceeded. Once that threshold has been surpassed, how-
ever, urinary copper excretion rises dramatically in a
heroic, but ultimately unsuccessful, effort by the
kidneys to rid the body of the excess copper.
Elevations in 24-hour urinary copper excretion can
be present in several conditions other than WD. Het-
erozygous carriers, who have one defective copy of
the ATP7B gene but neither develop symptomatic
WD nor require any treatment, may have modestly
elevated urinary copper levels, although they typically
do not exceed 100 mg/day (Brewer, 2001). Urinary cop-
per levels may also become elevated in primary biliary
cirrhosis and other obstructive liver diseases (LaRusso
et al., 1976; Frommer, 1981).
Despite these limitations, a 24-hour urinary copper
determination is probably the single best screening test
for WD in symptomatic patients. The 24-hour nature
of the test makes it cumbersome and the collection pro-
cess itself should be meticulous, but the information it
provides is invaluable in assessing individuals for possi-
ble WD. To ensure accuracy, Brewer routinely obtains
two separate 24-hour urinary copper determinations
when evaluating persons for possible WD and maintains
that 24-hour urinary copper level will always be elevated
in individuals with symptomatic WD (Brewer, 2001).
Other investigators have reported 24-hour urinary
copper levels to be elevated in only 68–88% of symp-
tomatic WD patients at the time of diagnosis (Steindl
et al., 1997; Gow et al., 2000), but Brewer (2001) force-
fully suggests that inadequate laboratory quality control
is responsible for the discrepancy.
A number of potential sources for contamination
during copper collection have been detailed (Mak and
Lam, 2008). Rinsing collection bottles with tap water
may falsely elevate copper if the tap water itself has a
high copper content. Funnels and urine collection bags
for pediatric patients may also be sources of copper
contamination, as are Foley catheters.
The penicillamine challenge test, during which the
subject receives a total of 1000 mg penicillamine over a
24-hour period during which urine for measurement of
copper is collected, has been advocated as a useful test
in evaluation of individuals for possible WD (Martins
da Costa et al., 1992; Foruny et al., 2008). However, some
investigators do not regard the test as useful (Gaffney
et al., 2000; Brewer, 2001), while others regard the
test as valuable in patients with active liver disease but
unreliable in asymptomatic siblings of WD patients
(Müller et al., 2007).
Serum copper
Although routine serum copper levels, which measure
total serum copper, are characteristically low in patients
with WD, they are actually of little diagnostic value.
Under normal conditions, copper bound to ceruloplasmin
has generally been considered to represent approximately
90% of serum copper (Brewer, 2001), although a recent
report suggested that the percentage of free copper
may be higher than generally accepted (Twomey et al.,
2007). Although this percentage is somewhat lower in
WD, total serum copper still largely reflects ceruloplas-
min concentrations and is low in WD simply because of
the marked reduction in ceruloplasmin (Yarze et al.,
1992; Brewer, 2001). In a patient with fulminant hepatic
failure, however, this changes dramatically and serum
copper levels become markedly elevated due to the
sudden release of copper from tissue stores (Roberts
and Schilsky, 2008).
Free (nonceruloplasmin-bound) copper
Unlike routine serum copper determination, which mea-
sures both the copper bound to ceruloplasmin and that
which is unbound or loosely complexed with albumin,
determination of free copper measures just the portion
of copper that is not bound to ceruloplasmin and thus is
available for deposition in tissues (Yarze et al., 1992). This
portion of copper is typically elevated in WD and has been
used as a screening test (Stremmel et al., 1991). It may also
be used to monitor response and compliance with therapy.
Generally, the serum free copper level is calculated
rather than directly measured. Total serum copper and
ceruloplasmin levels obtained simultaneously are
needed to make this calculation. In the calculation,
the number for the ceruloplasmin level (reported in
mg/dL) is multiplied by 3 and subtracted from the total
serum copper level (reported in mg/dL), producing the
calculated free copper level, which is 10–15 mg/dL in
normal individuals (Brewer, 2001). It is important to
note, however, that cut-off levels may vary from labora-
tory to laboratory (Twomey et al., 2008). This level is
higher than 25 mg/dL in most persons with untreated
WD (Roberts and Schilsky, 2008).
A number of investigators have commented on the
vagaries of calculated free copper determinations and
suggested alternate methods (Twomey et al., 2006).
In a potential solution to these problems, a method
 WILSON’S DISEASE
for direct measurement of free copper concentrations in
serum or plasma by means of inductively coupled mass
spectrometry has recently been reported (McMillin
et al., 2009). Some investigators, however, hold the
opinion that free copper levels, regardless of how they
are determined, are not helpful and only add to diag-
nostic confusion (Mak and Lam, 2008).
Neuroimaging studies
Both magnetic resonance imaging (MRI) and computed
tomography (CT) frequently demonstrate abnormalities
in patients with WD. Of the two, MRI is the more
sensitive. Some reports suggest that MRI is abnormal
in 100% of individuals who have developed neurological
dysfunction (Thuomas et al., 1993; Roh et al., 1994;
Saatci et al., 1997; Sinha et al., 2006). A variety of
changes can be seen on MRI in WD. Parenchymal
atrophy and alterations in signal intensity are the most
characteristic. The most consistent abnormalities occur
in the basal ganglia, but brainstem and thalamus
frequently show changes (Selwa et al., 1993; Magalhaes
et al., 1994; Sinha et al., 2006). In one study of 100 WD
patients, signal abnormalities were noted in the putamen
in 72%, caudate 61%, thalami 58%, midbrain 49%, cere-
bral white matter 25%, pons 20%, medulla 12%, cerebel-
lum 10%, and cortex 9% (Sinha et al., 2006). The most
characteristic signal changes are the presence of
increased signal intensity on T2-weighted images and
reduced signal intensity on T1-weighted images (Sinha
et al., 2006). Sometimes an area of increased signal inten-
sity surrounds an area of decreased signal intensity
(Magalhaes et al., 1994). The increased signal intensity
may be produced by edema or demyelination, whereas
deposition of either copper or iron may be responsible
for the region of reduced signal intensity (Magalhaes
et al., 1994; Alanen et al., 1999).
Several distinctive neuroimaging abnormalities have
been described. The “face of the giant panda” sign in
the midbrain, seen on T2-weighted images, is produced
by increased signal intensity in the midbrain tegmentum
surrounding the normally hypointense red nuclei (Hitoshi
et al., 1991; Liebeskind et al., 2003). Changes in the pons
said to resemble the cub of the giant panda (or face of
the miniature panda) have also been described (Kuruvilla
and Joseph, 2000; Das and Ray, 2006). Bilateral bright-
ness and thickening of the claustrum have been described
as distinctive for WD and christened the “bright claus-
trum sign” (Sener, 1993). However, these findings are
present in only a small percentage of patients with WD,
which limits their diagnostic utility (King et al., 1996;
Sinha et al., 2006).
Neuroimaging changes similar to those seen in WD
can occur in a number of other disease entities such as
693
Leigh disease, hypoxic-ischemic encephalopathy, methyl
alcohol poisoning, Japanese B encephalitis, and in the
osmotic disequilibrium syndrome with extrapontine
myelinolysis (Das and Ray, 2006). The clinical features
of these entities should distinguish them from WD.
Other neuroimaging modalities have been investi-
gated in WD. Positron emission tomography (PET)
scanning with 18F-deoxyglucose (Hawkins et al., 1987;
Hefter et al., 1993; Hermann et al., 2002), 18F-dopa
(Snow et al., 1991), and other dopaminergic markers
(Schwarz et al., 1994; Westermark et al., 1995) demon-
strated abnormalities in WD, but these tests are not yet
routinely available in clinical practice. Proton MR spec-
troscopy has also been studied in WD, with conflicting
results (Alanen et al., 1999; Jayasundar et al., 2002;
Tarnacka et al., 2008). Pilot studies with transcranial
sonography suggest that this procedure may be useful
in identifying copper accumulation in the basal ganglia
preclinically, but more extensive evaluation is needed
before this can be routinely employed (Walter et al.,
2007; Bartova et al., 2008).
Electrophysiologic studies
Evoked potentials of various types may be abnormal in
WD, often early in the course, even before the appear-
ance of KFRs or MRI abnormalities (Topcu et al.,
2002). However, the abnormalities are nonspecific, with
no clear diagnostic value (Grimm et al., 1992). They are
not routinely obtained in the evaluation of WD.
Radiocopper incorporation
Measurement of the incorporation of radioactive copper
(64Cu) into ceruloplasmin has also been employed in the
diagnostic evaluation of WD. When 64Cu is adminis-
tered intravenously or orally to normal individuals, there
is an initial rise in 64Cu as it enters the blood stream and
is complexed with albumin and amino acids. Levels then
drop as the 64Cu is cleared by the liver, but this is fol-
lowed by a secondary rise of 64Cu in the blood that peaks
at approximately 48 hours. This secondary rise is the
result of 64Cu being incorporated into newly formed
ceruloplasmin and released into the circulation. This
does not occur in WD because the 64Cu cannot be
incorporated into ceruloplasmin due to the defective
ATP7B protein. The potential value in this test lies in that
it will be abnormal in WD even if the ceruloplasmin level
is normal or near-normal (Sternlieb and Scheinberg,
1979). However, difficulty obtaining the radioactive
isotope limits the availability, and overlap of values
between individuals with WD and heterozygous carriers
limits the utility of this procedure (Brewer, 2001; Roberts
and Schilsky, 2008).
694 R.F. PFEIFFER
Cerebrospinal fluid copper
Cerebrospinal fluid (CSF) copper levels are elevated in
persons with WD and neurological dysfunction and
decline with successful symptomatic treatment (Weisner
et al., 1987). Some investigators suggested that CSF
copper levels may be the most accurate reflection of brain
copper load (Hartard et al., 1993). In one report in which
CSF copper concentrations were measured in four WD
patients, the average treatment time to normalize CSF
copper content (< 20 mg/L) was 47 months (Stuerenburg,
2000). Measurement of CSF copper is not performed
in routine clinical practice and should be considered
strictly a research tool.
DIAGNOSTIC TESTING GUIDELINES
Hepatic presentation
In suspected WD presenting with hepatic dysfunction,
KFRs are not consistently present and their absence
does not exclude the diagnosis of WD. However, the
24-hour urinary copper content is usually elevated
and serum ceruloplasmin is typically reduced. Diagnos-
tic confusion can sometimes be caused by individuals
with longstanding obstructive liver disease or hepatic
failure of any etiology, because hepatic copper content
can sometimes rise to WD levels in such situations. In
suspected WD presenting with hepatic dysfunction,
liver biopsy is generally warranted to confirm the diag-
nosis by documenting elevated hepatic copper content
and to assess the degree of hepatic injury. It is likely
that technical advances will make genetic testing com-
mercially feasible for diagnostic testing in WD and it
will become the diagnostic test of choice.
Neuropsychiatric presentation
In suspected WD presenting with either neurologic or
psychiatric dysfunction, the presence of KFRs, coupled
with elevated 24-hour urinary copper levels and reduced
ceruloplasmin concentrations, virtually confirms the
diagnosis of WD and renders liver biopsy unnecessary.
However, in the occasional situation where either the
24-hour urine or the ceruloplasmin level is inconclusive,
liver biopsy may be necessary. If genetic testing becomes
commercially feasible, it will become the diagnostic test
of choice.
TREATMENT
Dietary therapy
Dietary restriction of copper intake has not been a suc-
cessful treatment approach in WD. It is difficult to
achieve and has not been demonstrated to be effective
in most instances. Exceptions to this generalization
have been reported in individuals with WD who have
been able to control WD effectively by a strict lactove-
getarian diet without additional therapy, presumably
because their increased dietary fiber and phytate suffi-
ciently reduced dietary copper bioavailability (Brewer
et al., 1993). Despite this negative dietary picture, some
investigators recommend that individuals with WD
avoid certain high-copper-content foods such as shell-
fish, liver, nuts, chocolate, and mushrooms (Brewer,
2001; Roberts and Schilsky, 2008).
Other sources of copper ingestion merit consider-
ation. Copper content in primary drinking sources (home,
work, school) of an individual with WD should be
measured, and, if the level is greater than 0.1 ppm, alter-
native water sources, such as bottled water, should be
used (Brewer, 2001). Brewer (2001) advises that eleva-
tions in this range may be found in approximately 10%
of WD patients. Domestic water softeners also increase
the copper content of water (Yarze et al., 1992). Of
course, copper-containing vitamins or mineral supple-
ments should be avoided by WD patients.
Inhibition of intestinal copper absorption
POTASSIUM
Potassium iodide or sulfide was employed in the past to
decrease copper absorption by forming insoluble copper
iodide or copper sulfate. However, this approach was
not effective and is no longer used.
ZINC
In contrast to potassium, the oral administration of
zinc has proven to be a successful means to inhibit
intestinal absorption of copper. Zinc may be adminis-
tered as zinc acetate, sulfate, or gluconate. Its effect
on copper absorption is mediated through the cyste-
ine-rich 61-amino-acid protein, metallothionein, which is
present in many body tissues, including brain, liver, and
intestinal cells (Ebadi et al., 1989, 1991; Ebadi, 1991).
Metallothionein, as a zinc-binding ligand, is important
for zinc homeostasis and transport (Ebadi, 1991). When
administered orally, zinc is absorbed by the intestinal
enterocytes and induces metallothionein formation. For
effective absorption to occur, however, zinc must be
administered on an empty stomach. The induced metal-
lothionein, in turn, binds zinc and inhibits its intestinal
absorption by trapping it within the enterocytes (Brewer
et al., 1983). However, while metallothionein has a high
affinity for zinc, it has an even higher affinity for copper
(Day et al., 1981) and the induced metallothionein also
binds dietary copper and traps it within the enterocytes
(Hall et al., 1979). The bound zinc and copper remain
trapped and stored within their enterocytic prisons until
 WILSON’S DISEASE
the cells are sloughed and excreted in the feces (Brewer
and Yuzbasiyan-Gurkan, 1992; Brewer et al., 1983). This
zinc-induced, metallothionein-mediated copper trapping
results in a small, but significant, negative copper bal-
ance, which is the basis for its efficacy in the treatment
of WD. The induction of metallothionein is a rather slow
process so its effect on copper absorption does not
become evident for 1–2 weeks.
In the initial years following its introduction for the
treatment of WD, the negative copper balance induced
by zinc was believed to be too small for zinc to be effec-
tive as monotherapy in individuals with symptomatic
WD (Brewer, 2001; Schilsky, 2001). Instead, its use was
limited to presymptomatic individuals, who had been
diagnosed with WD but had not yet developed clinical
symptoms (Brewer and Yuzbasiyan-Gurkan, 1992;
Brewer, 2006; Hoogenraad, 2006). With further experi-
ence, the use of zinc as “maintenance” therapy follow-
ing initial treatment of neurologically symptomatic
individuals with other more potent decoppering agents
has become accepted (Hoogenraad, 1996; Brewer,
2001; Mak and Lam, 2008; Roberts and Schilsky,
2008). Some investigators now even consider zinc to
be first-line therapy for WD (Hoogenraad, 2006),
although others still view zinc monotherapy as contro-
versial (Subramanian et al., 2002).
One of the appealing attributes of zinc is that it is well
tolerated, with little toxicity. It has also been reported to
be safe and effective in both children and pregnant
women (Brewer et al., 2000, 2001). Adverse effects
rarely occur. Gastric irritation, typically with the first
morning dose, may occasionally be present and is more
frequent with zinc sulfate than with zinc acetate (Brewer
and Yuzbasiyan-Gurkan, 1992). Taking the zinc with a
small protein-based snack may circumvent gastric upset
without significantly compromising treatment efficacy,
although it remains preferable to take zinc on an empty
stomach (Brewer, 2001).
Some laboratory abnormalities have been described
with zinc therapy. Serum amylase and lipase levels may
increase early in the course of zinc therapy, as may alka-
line phosphatase levels, all later returning to normal
(Yuzbasiyan-Gurkan et al., 1989). Zinc has been reported
to lower high-density lipoprotein cholesterol in both men
and women by approximately 10% (Hooper et al., 1980;
Brewer et al., 1992).
Other, potentially more significant problems have
rarely been reported with zinc therapy. Sideroblastic
anemia from impaired iron utilization may occur (Simon
et al., 1988). Although its occurrence is disputed (Brewer,
1999; LeWitt, 1999; Walshe, 1999), both neurological
and hepatic deterioration, with a fatal outcome in at least
one instance, have been reported in symptomatic indivi-
duals (Lang et al., 1993; Walshe and Munro, 1995). In
695
presymptomatic individuals, acute hepatitis has been
noted following institution of zinc therapy (Castilla-
Higuero et al., 2000) and the emergence of clinical symp-
toms has occurred (Mishra et al., 2008).
A dosage of 50 mg of elemental zinc three times daily
is utilized in treating both presymptomatic and symptom-
atic WD. Dosage designation can be confusing. Zinc
sulfate tablets, which are readily available without pre-
scription in the USA, are listed as containing 220 mg of
zinc sulfate salt, but this translates to 50 mg of elemental
zinc. Zinc acetate and zinc gluconate are labeled by their
elemental zinc content.
Copper chelation therapy
BRITISH ANTI-LEWISITE
Dimercaprol, or British anti-Lewisite (BAL) is included
for historical purposes. It was the initial copper-chelating
agent used in the treatment of WD, but the necessity to
administer it parenterally and the development of safer
agents have rendered it virtually obsolete except for
exceedingly rare instances (Walshe and Munro, 1995).
PENICILLAMINE
Penicillamine (dimethylcysteine) is a metabolic bypro-
duct of penicillin that avidly chelates copper and holds
it until the complexed copper is excreted in the urine.
Additional actions, such as inducing metallothionein,
have been proposed (Yarze et al., 1992) but are of uncer-
tain importance. Copper chelation with cupriuresis
clearly seems to be of primary importance. Penicilla-
mine was introduced as a treatment for WD by Walshe
in 1956. It rapidly became the treatment of choice for
WD and has remained so until recent years, when its
safety has come under increasingly strident challenge.
Like zinc, penicillamine should be administered on an
empty stomach. Its bioavailability is reduced by approx-
imately 50% if ingested with food (Schuna et al., 1983).
The traditionally recommended dose is 1–2 g daily,
divided into four doses, but lower doses are recom-
mended by some. Concomitant administration of
pyridoxine has been recommended because penicilla-
mine is a pyridoxine antagonist (Marsden, 1987; Yarze
et al., 1992), but others believe this is unnecessary except
in special circumstances such as pregnancy, during a
growth spurt, or when there is dietary pyridoxine defi-
ciency (Gibbs and Walshe, 1969; Walshe and Yealland,
1993).
Improvement in function following initiation of
penicillamine therapy does not become evident for
2–3 months, although it may begin as early as 2 weeks
(Deiss, 1983). Clinical improvement may gradually
increase for a period of time that may stretch as long
696 R.F. PFEIFFER
as 1–2 years (Brewer and Yuzbasiyan-Gurkan, 1992).
Over time, improvement in virtually all symptoms
and signs of WD may occur, although not all at equal
speed or equally well. KFRs slowly recede and eventually
disappear over 8–12 months (Aggarwal et al., 2009), in a
sequence inverse to their appearance (Sussman and
Scheinberg, 1969). Sunflower cataracts clear, and often
do so more rapidly than KFRs (Sussman and Scheinberg,
1969; Wiebers et al., 1977). Neuropsychiatric features
demonstrate considerable variability in their speed and
completeness of improvement. Tremor and cerebellar
dysfunction improve more readily than dystonia. Some
features, such as dysarthria and the fixed smile, or
risus sardonicus, may not improve at all with treatment.
Psychiatric symptoms improve with penicillamine, but
often not with the speed or with the completeness that
is evident with neurological dysfunction (Akil and
Brewer, 1995). Psychometric testing results reflect this
(Goldstein et al., 1968). Neuroimaging abnormalities may
improve during penicillamine treatment. This is true of
both CT (Williams and Walshe, 1981) and MRI (Nazer
et al., 1993; Thuomas et al., 1993; Roh et al., 1994).
Although penicillamine is very effective in remov-
ing copper from the body, it is also capable of produc-
ing serious and potentially disastrous adverse effects.
Acute sensitivity reactions develop in 20–30% of
individuals on penicillamine (Sternlieb and Scheinberg,
1964; Haggstrom et al., 1980). The sensitivity reactions
develop within 2 weeks of therapy initiation. They consist
of skin rash, fever, eosinophilia, thrombocytopenia, leu-
kopenia, and lymphadenopathy. Penicillamine-induced
agranulocytosis may be fatal (Corcos et al., 1964). Penicil-
lamine should be promptly discontinued if an acute sen-
sitivity reaction is recognized. In the past, reinstitution
of penicillamine at a lower dose and in conjunction with
steroid administration was attempted after resolution
of the acute reaction, but with the current availability
of alternative medications, such as trientine, this is no
longer necessary or advisable (Roberts and Schilsky,
2008).
A variety of other potential adverse affects may occur
in the setting of chronic penicillamine therapy, some-
times as long as 30 years after initiation of treatment
(Walshe and Yealland, 1993). Nephrotic syndrome
(Hirschman and Isselbacher, 1965), Goodpasture’s syn-
drome (Sternlieb et al., 1975), a lupus-like syndrome
(Walshe, 1981a, b), a myasthenia-like syndrome (Czlon-
kowska, 1975), acute polyarthritis (Golding and Walshe,
1977), thrombocytopenia (Scheinberg and Sternlieb,
1984), and retinal hemorrhages (Bigger, 1968) have all
been reported. Loss of sense of taste may develop during
penicillamine treatment and may improve with zinc
administration (Henkin et al., 1967; Shoulson et al.,
1983). Serum immunoglobulin A deficiency has been
described with penicillamine (Proesman et al., 1976). Pen-
icillamine may also produce an array of dermatologic
problems. Recurrent subcutaneous bleeding as a result
of penicillamine-induced inhibition of collagen and elas-
tin cross-linking may occur after repeated incidental
trauma and is called penicillamine dermatopathy (Nimni,
1977; Sternlieb et al., 1981). Elastosis perforans
serpiginosa (Pass et al., 1973; Kirsch and Hukill, 1977),
pemphigus (Eisenberg et al., 1981), and aphthous
stomatitis (Bennett and Harbilas, 1967) are additional
penicillamine-induced dermatologic processes. Because
penicillamine can impair wound healing, some have sug-
gested that dosage be reduced to 250–500 mg/day during
any perioperative period (Morris et al., 1969; Scheinberg
and Sternlieb, 1984).
A potentially more troublesome problem with penicil-
lamine therapy has come to the forefront in recent years.
Penicillamine has the propensity to produce initial deteri-
oration in neurological function when treatment
is undertaken. Emergence of neurological dysfunction
in previously asymptomatic individuals has also been
reported following initiation of penicillamine therapy
(Glass et al., 1990; Brewer et al., 1994b). That neurological
deterioration may occur following penicillamine expo-
sure is not disputed; how frequently it develops is, how-
ever, a source of controversy (Brewer, 1999; LeWitt,
1999; Walshe, 1999). Walshe and Yealland (1993) noted it
in 22% of 137 WD patients treated with penicillamine,
while Brewer reported it in 52% of 25 patients in a
retrospective study (Brewer et al., 1987; Brewer, 2001).
He stressed that 50% of those in whom neurological
deterioration occurred upon initiation of therapy did not
fully recover to their baseline level of functioning. A fatal
outcome of this type of deterioration, in the form of sta-
tus dystonicus, has also been reported following initiation
of penicillamine treatment (Svetel et al., 2001b). Why this
deterioration in neurological function develops is not cer-
tain. Mobilization of copper from the liver with
subsequent redistribution to the brain has been suggested
(Brewer et al., 1987) but studies of CSF copper levels dur-
ing this form of neurological deterioration do not appear
to confirm this hypothesis (Hartard et al., 1993).
The risk that penicillamine might induce irreversible
neurological deterioration in individuals following its
initiation has led to a divergence in opinion as to the
proper role for penicillamine in the treatment of WD.
Some investigators suggest continuing to use penicilla-
mine but with lower initiating doses, while others recom-
mend treatment induction with other, ostensibly safer
medications such as trientine, zinc, or tetrathiomolyb-
date. Brewer advocates that penicillamine not be used
at all in the treatment of WD, except possibly in the
patient with acute, fulminant hepatic failure while await-
ing liver transplantation (Brewer, 1999, 2001).
 WILSON’S DISEASE
TRIENTINE
Trientine (triethylene tetramine dihydrochloride) is a
copper-chelating agent with a mechanism of action simi-
lar to penicillamine (Walshe, 1969, 1973, 1982, 1983). It
differs from penicillamine, however, in that trientine
competes for copper bound to albumin and does not
enter the liver (Sarkar et al., 1977). Trientine also evokes
a gentler decoppering, compared with penicillamine,
which may make it less prone to trigger deterioration in
neurological function. This perceived higher safety level
of trientine, compared with penicillamine, has led to its
increasing use as a first-line treatment of WD presenting
with neurological dysfunction (Brewer, 2001, 2004;
Schilsky, 2001).
As is true with zinc and penicillamine, trientine
should be taken on an empty stomach. The daily dose
is 750–2000 mg/day, divided into three doses (Yarze
et al., 1992). Once-daily trientine administration has been
successfully employed by some patients during mainte-
nance therapy as a means of improving medication
compliance, but this should not be considered the pre-
ferred regimen for most patients, nor should it be used
for initiation of treatment (Fox and Schilsky, 2008).
Adverse effects from trientine occur but appear to
be less frequent than with penicillamine. Both lupus
nephritis and sideroblastic anemia have been reported
with trientine (Walshe, 1982; Condamine et al., 1993).
In addition to chelating copper, trientine will also chelate
and form a toxic complex with iron, so concomitant
administration of iron and trientine should be avoided
(Roberts and Schilsky, 2008).
Combination agents
TETRATHIOMOLYBDATE
Ammonium tetrathiomolybdate (TM) was first tested
for the treatment of WD in 1984 (Walshe, 1999), but it
remains an experimental treatment modality, unavailable
for general use. Because of the significant amount of
attention that has been directed to TM, especially by
Brewer (2001, 2009), TM is discussed despite the absence
of regulatory approval. TM has a distinct, dual mecha-
nism of action that separates and distinguishes it from
other available treatment modalities (Brewer, 2001;
Brewer et al., 1994a). It functions both to inhibit copper
absorption from the gastrointestinal tract and to complex
with copper in the blood stream, reducing the copper load
of a WD patient both in the gut and systemically.
Inhibition of gastrointestinal absorption of copper by
TM is accomplished in a manner distinctly different
from that of zinc. In the gut lumen, TM forms a tripar-
tite complex with copper and albumin, which cannot be
absorbed by intestinal mucosal cells and is eliminated in
697
the feces (Brewer et al., 1994a; Brewer, 2001). Because it
does not involve metallothionein induction, the effect of
TM in reducing copper absorption is evident immedi-
ately upon its administration.
The second mechanism by which TM reduces copper
load is by its action on copper within the blood stream.
TM forms the same tripartite complex with albumin
and unbound (free) copper and renders the copper inac-
tive (Brewer et al., 1994a; Brewer, 2001). In addition to
its action within the blood stream, TM enters the liver
and binds up to 6 copper ions by forming copper-
molybdenum multimetallic clusters (George et al., 2003;
Zhang et al., 2009).
The manner in which TM has been investigated to date
is distinctly different from other conventional WD treat-
ment modalities. TM has been evaluated strictly as an
induction agent that is employed for an 8-week course
and then discontinued and replaced by another agent,
such as zinc, for ongoing chronic therapy (Brewer,
2001). In WD patients with neurological dysfunction,
administration of TM in this fashion has produced
prompt and significant reduction in unbound (free)
copper within the blood stream (Brewer et al., 1991,
1994a, 1996; Brewer, 2001).
TM has been well tolerated when administered as
induction therapy. However, some potentially significant
adverse effects have been noted. Bone marrow depres-
sion, with resultant anemia and occasional leukopenia,
presumably secondary to bone marrow copper depletion,
has been documented (Brewer, 2001). It resolves with
discontinuation of the TM. Laboratory abnormalities in
the form of mild transaminase elevations have been
noted with TM therapy (Brewer, 2001). Some recom-
mend that TM not be used in children or adolescents
for more than short courses because in animal studies
TM has been demonstrated to produce epiphyseal dam-
age in growing bone (Spence et al., 1980; Walshe and
Yealland, 1993).
One relative drawback to the use of TM is its rather
complicated dosage regimen. Six daily doses of 20 mg
each are employed: three doses at mealtimes to complex
dietary copper and reduce its gastrointestinal absorption,
and three doses between mealtimes to allow maximum
absorption of TM itself, which optimizes its ability to
complex copper within the blood stream (Brewer, 2001).
Patient compliance is severely tested with this dosage
regimen.
Liver transplantation
The most dreaded complication of WD is the develop-
ment of fulminant hepatic failure. The mortality rate
of fulminant hepatic failure in WD is virtually 100% if
treatment is confined to medical management (Shafer
698 R.F. PFEIFFER
and Shaw, 1989; Rela et al., 1993; Schilsky et al., 1994).
Orthotopic liver transplantation (OLT) is the one effec-
tive treatment for this complication of WD. While
fulminant hepatic failure is the primary indication for
the performance of OLT in WD, the procedure may also
be appropriately employed in patients with chronic
severe hepatic insufficiency unresponsive to medical
management (Schilsky et al., 1994).
Schilsky and colleagues (1994) reviewed the experi-
ence with 55 patients with WD who underwent OLT
at 15 transplant centers in the USA and three in
Europe. The survival rate at 1 year was 79%. This rate
is similar to that reported by others (Chen and Kuo,
1993; Rela et al., 1993). With growing experience and
surgical refinements, the survival rate has become even
more impressive. In a recent report, a survival rate of
100% with a median follow-up time of 10 years was
reported for 13 WD patients transplanted at a single
center (Pabón et al., 2008). Beyond the truly remark-
able improvement in survival that OLT provides for
WD patients who have developed fulminant hepatic
failure, the fact that the transplanted liver is free of
the genetic defect that characterizes WD and contains
normally functioning ATP7B protein means that cop-
per metabolism normalizes following OLT and
continued chelation or other medical therapy generally
is no longer necessary (Rela et al., 1993; Schilsky et al.,
1994; Brewer, 2001). In this sense, OLT is curative for
the individual with WD. Several qualifications or
caveats must be appended. Transplanted patients still
retain their genetic abnormality in all other body tis-
sues and will pass on the WD trait to all children.
Furthermore, if the transplanted liver was received
from a parent as a living related donor, the trans-
planted liver will bear the genetic makeup of a hetero-
zygote for WD and may not have entirely normal liver
function (Komatsu et al., 2002).
While virtually all features of WD improve following
OLT, the appearance of neurological symptoms shortly
following OLT has been reported (Litwin et al., 2008).
Acute central nervous system injury as a consequence
of massive release of copper from the damaged WD
liver just prior to and during its removal was presumed
to be responsible.
While OLT has primarily been utilized in WD for the
emergent treatment of patients with fulminant hepatic
failure, its potential utility in treating the patient with sta-
ble liver function but severe neurological dysfunction
that is progressing despite optimal medical management
has been considered. Case reports of OLT performed
for this indication have been published (Mason et al.,
1993; Stracciari et al., 2000), but this treatment indication
is still considered to be experimental and not routine
standard of care.
An important limiting factor in the utilization of
OLT in the treatment of fulminant hepatic failure in
WD (and other diseases) is the very limited availability
of donor organs. Given the dramatic survival rates
for WD patients who undergo OLT, it is, tragically,
all too frequent for patients to die before a donor
liver becomes available. This sad fact has led to the
exploration of alternatives to the usual method of
liver donation from unrelated, deceased donors. Living
related liver transplantation, in which the donor is a
living relative of the affected patient and donates
part of his or her liver, has been successfully employed
in WD (Cheng et al., 2009; Yoshitoshi et al., 2009).
More temporary, or bridging methods to support indi-
viduals until a donor liver becomes available have been
investigated. A form of modified dialysis in which
albumin is utilized as a dialysate, the Molecular Adsor-
bents Recirculating System (MARS), has been success-
fully employed for this purpose (Kreymann et al.,
1999; Sen et al., 2002; Chiu et al., 2008). Repeated
use of MARS can significantly reduce serum copper
levels and improve hepatic encephalopathy. Single-pass
albumin dialysis is another temporizing treatment
approach that has been reported to be successful (Sen
et al., 2002; Collins et al., 2008). Plasmapheresis has
provided beneficial results in this situation (Kiss
et al., 1998; Jhang et al., 2007), even if only a single
session is possible (Hursitoglu et al., 2009). In an even
more experimental approach, extracorporeal perfusion
through porcine liver cells has been employed (Mazar-
iegos et al., 2001).
Other surgical treatment approaches have been
employed in the treatment of WD. Unilateral
stereotactic thalamotomy was successful in reducing
severe bilateral postural-kinetic tremor in 1 patient (Pal
et al., 2007). A possible glimpse into the future may
have been provided by recent reports of the success of
hepatocyte transplantation with subsequent hepatic
repopulation in the Long–Evans rat model of WD
(Malhi et al., 2002) and transient effectiveness of ade-
novirus-mediated gene transfer therapy in the same ani-
mal model (Ha-Hao et al., 2002).
TREATMENT GUIDELINES
Asymptomatic patients
In the individual who is asymptomatic, most now recom-
mend that therapy be initiated with zinc alone. The rela-
tive absence of adverse effects from zinc makes this
drug especially appealing in this situation. There is no
need to subject presymptomatic individuals to the risk
of adverse effects from the more potent copper chelating
agents.
 WILSON’S DISEASE
Hepatic presentation
In the individual with hepatic but not neurologic or
psychiatric dysfunction, simultaneous introduction of
both a chelating agent and zinc may be ideal. Penicilla-
mine has been the standard chelating agent used, but
trientine has gained favor over penicillamine in recent
years because of the perception that it is less likely
than penicillamine to induce neurological deterioration
upon initiation of treatment. Some might opt for zinc
monotherapy in this setting.
Neuropsychiatric presentation
No unequivocally clear consensus has developed for
treating the individual who has developed neurologic
or psychiatric dysfunction. It may well be that TM will
be regarded as the treatment of choice in this situation,
but TM remains an experimental treatment that has not
yet received the approval from regulatory agencies nec-
essary to permit its general use. Until then, the primary
choice to be made is whether to initiate therapy with
penicillamine or trientine. Both have their advocates,
but a growing preference for trientine seems evident.
Zinc is recommended by some investigators for initiation
of therapy, but most reserve its use in the neurologically
affected patient for maintenance therapy following
initial employment of a chelating agent.
Fulminant hepatic failure
For the individual with either fulminant hepatic failure
or severe, chronic liver failure, OLT may be the only
viable treatment option. Temporizing, bridging mea-
sures to be employed while awaiting donor liver avail-
ability are being evaluated, but should be considered
experimental.
Treatment monitoring
Adequate monitoring of patients following initiation of
treatment is an extremely important, but often neglected,
aspect of WD management. It is vital that patients
comply with the prescribed treatment regimen, but even
with close follow-up and extensive educational measures,
intermittent compliance problems become evident in 30%
of WD patients and severe compliance problems occur in
approximately 10%. Compliance with zinc therapy can be
assessed by measurement of 24-hour urinary zinc and
copper levels. A 24-hour urinary zinc level of less than
2 mg (normal is 0.1–0.4 mg) indicates inadequate compli-
ance (Brewer, 2001). Monitoring compliance with trien-
tine or penicillamine therapy is somewhat more
difficult, but a spike in a previously gradually decreasing
24-hour urinary copper level may indicate inadequate
699
compliance (Brewer, 2001). In patients with WD on
chronic, stable penicillamine therapy, the 24-hour urinary
copper level should be in the range of 200–500 mg/day;
levels below 200 mg/day may indicate either noncompli-
ance or overtreatment (Roberts and Schilsky, 2008).
The serum nonceruloplasmin (free) copper level can also
be a useful monitoring tool: elevation above 15 mg/dL
suggests inadequate compliance (Brewer, 2001; Roberts
and Schilsky, 2008).
It is important to remember that prolonged treat-
ment with zinc and chelating agents poses the risk of
actually inducing a copper deficiency state in the
patient. Anemia, sometimes with associated leukopenia,
may be the initial sign of copper deficiency (Brewer,
2001). In patients on zinc maintenance therapy, a 24-hour
urinary copper level below 35 mg/day is suggestive of
copper deficiency due to overtreatment (Brewer, 2001).
For individuals on trientine or penicillamine, a serum
nonceruloplasmin (free) copper level below 5mg/dL sug-
gests overtreatment (Brewer, 2001; Roberts and Schilsky,
2008).
A guideline for the diagnosis and treatment of WD,
approved by the American Association for the Study
of Liver Diseases, has been published and provides an
excellent indepth review with 23 specific diagnostic
and treatment recommendations (Roberts and Schilsky,
2008).
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