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