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436 Hepatology 2012
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(Abstract)
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Hepatology 1999;30:847-50. (Abstract)
Wilson’s Disease 437
26. Wilson’s Disease
Claus Niederau
Introduction
In 1912, Kinnear Wilson was the first to describe an inherited lethal disease
associated with progressive lenticular degeneration, chronic liver disease and
cirrhosis (Wilson 1912). In the same year, Kayser and Fleischer detected that
patients with Wilson’s Disease (WD) often have brownish corneal copper deposits
now called Kayser-Fleischer rings (Fleischer 1912).
WD is an autosomal recessive error of the metabolism. Its gene ATP7B encodes a
copper-transporting ATPase (Bull 1993, Tanzi 1993, Petrukhin 1993, Yamaguchi
1993). The genetic defect of the ATP7B protein reduces biliary copper excretion
leading to copper accumulation in the cornea and various organs including the liver,
brain and kidney. The alteration of the ATP7B protein also reduces the
incorporation of copper into ceruloplasmin. The corresponding presence of
apoceruloplasmin (ceruloplasmin with no copper incorporation) leads to a decrease
in circulating levels of ceruloplasmin due to the reduced half-life of the apoprotein.
Thus, despite copper accumulation in many organs, circulating levels of copper and
ceruloplasmin are decreased in most WD patients.
The prevalence of WD is rare, estimated at 3 per 100,000 population (Frysman
1990). The clinical presentation may vary. Some WD patients are diagnosed with
liver problems while others present with neurologic or psychiatric symptoms; many
patients show both hepatic and neurological disease (Figure 1). Episodes of
hemolysis and renal abnormalities may also occur. WD typically affects children
and younger adults, and is rarely seen in adults older than 40. WD is fatal unless
appropriately treated. Drugs for treatment of WD are copper chelators such as
penicillamine, and trientine (Walshe 1956). More recently, zinc has been used to
reduce intestinal copper absorption and to detoxify free circulating copper. Patients
with fulminant liver failure or decompensated cirrhosis may have to undergo liver
transplantation (LTX), which cures WD.
Clinical presentation
Screening for WD is useful only in families with an affected member. In all other
circumstances diagnostic procedures are only done when symptoms and findings
suggest WD. These include liver disease, neurological symptoms, renal
438 Hepatology 2012
abnormalities and episodes of hemolysis. WD is diagnosed in the vast majority of
patients between the ages of 5 and 35. There are rare reports of patients diagnosed at
ages 3-5 (Kalach 1993, Wilson 2000) and at ages of up to about 60 years (Gow
2000). Late-onset WD is a frequently overlooked condition (Ferenci 2007).
Diagnostic workup does not rely on a single test but includes identification of
corneal Kayser-Fleischer rings, reduced serum ceruloplasmin and copper as well as
a quantitative determination of liver copper concentration (Scheinberg 1952,
Walshe 1956, Saito 1987, Stremmel 1991, Roberts 2003) (Figure 2).
Figure 1. Clinical course of WD in 53 patients (modified from
Stremmel 1991).
Figure 2. Diagnostic workup for WD.
Genetic tests are usually only done in relatives of a confirmed WD patient. It is
easy to diagnose WD in subjects who present with liver cirrhosis, typical neurologic
manifestations and Kayser-Fleischer rings; many of these patients present at ages 5
to 35 and have decreased serum copper and ceruloplasmin (Sternlieb 1990).
However, a considerable number of WD patients present only with liver disease and
may not have Kayser-Fleischer rings or decreased serum levels of ceruloplasmin
(Steindl 1997). Under these circumstances diagnosis may be difficult; measurement
of 24 hour urinary copper excretion often helps to support the suspicion of WD.
Wilson’s Disease 439
Liver biopsy with measurement of quantitative copper concentration should be done
to corroborate the diagnosis (Stremmel 1991, Roberts 2003).
In general, WD patients diagnosed primarily with liver disease are children and
adolescents and are younger than those diagnosed due to neurological symptoms
(Merle 2007). Many patients who present only with CNS symptoms are 20-40 years
old. Patients with WD may present with a wide spectrum of liver disease ranging
from asymptomatic elevation of serum aminotransferases to fulminant liver failure.
Serum aminotransferases are elevated in most WD patients irrespective of age
(Schilsky 1991). Other WD patients may present with findings and symptoms of
autoimmune hepatitis including autoimmune antibodies and elevated IgG (Scott
1978, Milkiewicz 2000). The clinical picture might also resemble acute or chronic
viral hepatitis, without the viral serum markers. Even liver histology is not
predictive or typical for WD unless copper concentration is measured. Histological
findings may range from fatty liver changes to severe necro-inflammatory and
fibrotic disease and complete cirrhosis. In particular, children and adolescents with
chronic active hepatitis of unknown etiology or autoimmune hepatitis and adult
patients with a suspicion of autoimmune hepatitis or non-response to
immunosuppressants should be evaluated for WD (Roberts 2003).
WD has to be excluded in patients with fulminant liver failure of unknown
etiology, especially at ages under 35 years; WD patients with such presentation
usually have some sort of liver disease (Rector 1984, Ferlan-Maroult 1999, Roberts
2003) associated with Coombs-negative hemolytic anemia and severely increased
prothrombine time non-responsive to vitamin K and progressive renal failure (Sallie
1992). Some patients have bilirubin levels of more than 40 mg/dl while serum
alkaline phosphatase is normal or just slightly elevated (Berman 1991). In contrast
to many types of toxic liver failure, liver failure in WD usually does not start with
high increases in aminotransferases. In many WD patients AST levels exceed ALT
levels (Emre 2001, Berman 1991). In most cohorts, for unexplained reasons, the
ratio of females to males is approximately 2:1 (Roberts 2003). Serum ceruloplasmin
may be decreased while serum copper and 24-hour urinary excretion of copper is
usually elevated. It is extremely helpful when one can identify Kayser-Fleischer
rings in this situation; these patients need to be studied with a slit lamp by an
experienced ophthalmologist. Patients with acute liver failure need a diagnostic
workup as rapidly as possible; if there is a strong suspicion or diagnosis of WD, the
patient should be transferred to a transplant centre the same day.
Neurological symptoms in WD often resemble those seen in Parkinson’s disease
including tremor and rigor. Many patients report that symptoms start with problems
in handwriting and dysarthria. Neurological symptoms may be associated with
slight behavioural alterations, which may later proceed to manifest psychiatric
disease including depression, anxiety and psychosis. With the progression of CNS
involvement WD patients may develop seizures and pseudobulbar palsy associated
with severe dysphagia, aspiration and pneumonia. Although many older WD
patients present with neurological disease, the diagnostic workup often shows
significant liver involvement or even complete liver cirrhosis.
Renal involvement of WD may present with aminoaciduria and nephrolithiasis
(Azizi 1989, Nakada 1994, Cu 1996). There may be various other non-neurological
and non-hepatic complications of WD such as osteoporosis and arthritis,
440 Hepatology 2012
cardiomyopathy, pancreatitis, hypoparathyroidism, and miscarriages (for literature
see Roberts 2003).
Kayser-Fleischer rings are caused by corneal copper deposition (Figure 3).
Sometimes, one can see the rings directly as a band of brown pigment close to the
limbus. In other patients the ring can only be identified using a slit lamp. Very
rarely similar rings may be seen in non-WD patients, e.g., in some patients with
neonatal or chronic cholestasis (Tauber 1993). Kayser-Fleischer rings are detectable
in 50-60% of WD patients in most large cohorts (Tauber 1993, Roberts 2003).
Many young WD patients with liver disease do not have such rings (Giacchino
1997) whereas almost all patients with primarily neurologic symptoms do have
them (Steindl 1997). WD patients may also have other less specific eye changes
including sunflower cataracts (Cairns 1963). Kayser-Fleischer rings usually regress
with chelation therapy or after LTX (Stremmel 1991, Schilsky 1994).
Figure 3. Kayser-Fleischer ring in a patient with WD.
Diagnosis
Serum ceruloplasmin
Ceruloplasmin, the major circulating copper transporter, is synthesized and
secreted mainly by hepatocytes. The 132 kd protein consists of six copper atoms per
molecule of ceruloplasmin (holoceruloplasmin) while the remaining part of the
protein does not carry copper (apoceruloplasmin). Ceruloplasmin acts as an acute
phase reactant and may thus be increased by any inflammatory process; it may also
rise in pregnancy and with the use of estrogens and oral contraceptives. One also
needs to remember that the normal range of serum ceruloplasmin is age-dependent:
it is usually low in infants until the age of 6 months; in older children it may be
Wilson’s Disease 441
somewhat higher than in adults. As explained previously, serum levels of
ceruloplasmin are generally decreased in WD; however, this finding alone is
unreliable because low serum ceruloplasmin may be seen without WD and serum
ceruloplasmin may even be increased in severe WD and liver failure. Non-specific
reductions of ceruloplasmin are usually associated with protein deficiency or any
end-stage liver disease. Long-term parenteral nutrition may also lead to decreased
levels of ceruloplasmin. Low serum ceruloplasmin is also a hallmark of Menkes’
disease, a very rare X-linked inborn error of metabolism that leads to a defect in
copper transport due to mutations in ATP7A (Menkes 1999). Very rarely, one
cannot measure serum ceruloplasmin at all. This aceruloplasminemia is a very rare
genetic disease caused by mutations in the ceruloplasmin gene; however, patients
with aceruloplasminemia develop iron and not copper overload (Harris 1998).
Most patients with WD have a serum ceruloplasmin lower than 20 µg/dl; this
finding is diagnostic for WD however only when there are other findings such as a
Kayser-Fleischer corneal ring. In one prospective screening study, ceruloplasmin
was measured in 2867 patients presenting with liver disease: only 17 of them had
reduced ceruloplasmin levels and only 1 of these subjects had WD (Cauza 1997).
Thus decreased ceruloplasmin had a positive predictive value of only 6% in the
2867 patients tested. In two cohorts, about 20% of WD had normal ceruloplasmin
and no Kayser-Fleischer rings (Steindl 1997, Gow 2000). Most reports, however,
show that more than 90% of WD patients have a reduced serum ceruloplasmin
(Walshe 1989, Lau 1990, Stremmel 1991). Measurement of ceruloplasmin as a
single marker cannot reliably differentiate homozygotes from heterozygotes.
Serum copper
Corresponding to the decrease in serum ceruloplasmin, total serum copper is also
usually decreased in WD. Similar to the diagnostic problems in interpreting
ceruloplasmin data in WD patients with fulminant liver failure, serum copper may
also be normal in this situation – even if serum ceruloplasmin is decreased. In acute
liver failure circulating copper may in fact be elevated because it is massively
released from injured hepatocytes. If ceruloplasmin is reduced, a normal or elevated
serum copper usually suggests that there is an increase in free serum copper (not
bound to ceruloplasmin). The free copper concentration calculated from total copper
and ceruloplasmin values has also been proposed as a diagnostic test and for
monitoring of WD. It is elevated above 25 µg/dL in most untreated patients (normal
values are below 10-15 µg/dL). The amount of copper associated with
ceruloplasmin is 3.15 µg of copper per mg of ceruloplasmin. Thus free copper is the
difference between the total serum copper in µg/dL and 3 times the ceruloplasmin
concentration in mg/dl (Roberts 1998).
Increases in serum free copper, however, are not specific for WD and can be seen
in all kinds of acute liver failure as well as in marked cholestasis (Gross 1985,
Martins 1992). The calculation of the free copper concentration critically depends
on the adequacy of the methods used for measuring total serum copper and
ceruloplasmin; often labs simply state that one of the tests is below a certain value,
which makes it impossible to calculate the amount of free copper.
442 Hepatology 2012
Urinary copper excretion
Most WD patients have an increase in urinary copper excretion above 100 µg/24
hours, which is thought to represent the increase in circulating free copper (not
bound to ceruloplasmin). Some studies suggest that about 20% of WD patients may
have 24-hr urinary copper excretion between 40-100 µg/24 h (Steindl 1997,
Giacchino1997, Gow 2000, Roberts 2003). However, some increase in urinary
copper excretion can be found in severe cholestasis, chronic active hepatitis and
autoimmune hepatitis (Frommer 1981). It has been suggested that urinary copper
excretion stimulated by penicillamine may be more useful than the non-stimulating
test. In children 500 mg of oral penicillamine is usually given at the beginning and
then at 12 hours during the 24-hour urine collection. All WD children looked at had
levels above 1600 µg copper/24 h and all patients with other liver diseases including
autoimmune hepatitis and cholestatic liver disease had lower values. It is not clear
whether this test has a similar discriminative power in adults where it has been used
in various modifications (Tu 1967, Frommer 1981).
Hepatic copper concentration
Hepatic copper content above 250 µg/g dry weight liver is still the gold standard for
diagnosis of WD and is not seen in heterozygotes or other liver diseases with the
exception of Indian childhood cirrhosis (Martins 1992). Biopsies (larger than 1 cm
in length) for measurements of hepatic copper determination should be taken with a
disposable Tru-Cut needle, placed dry in a copper-free container and shipped frozen
(Song 2000, Roberts 2003).
Radiolabelled copper
In WD, incorporation of radiolabelled copper into ceruloplasmin is significantly
reduced. This test is rarely used because of the difficulty in obtaining the isotope
and because of legal restrictions.
Liver biopsy findings
Histological findings in WD range from some steatosis and hepatocellular necrosis
to the picture as seen in severe autoimmune hepatitis with fibrosis and cirrhosis.
Patients diagnosed at a young age usually have extensive liver disease; older
patients who first present with neurological symptoms often have abnormalities in
liver biopsy as well (Stremmel 1991, Steindl 1997, Merle 2007). Detection of
copper in hepatocytes, e.g., by staining with rhodamin using routine histochemistry
does not allow a diagnosis of WD (Geller 2000) (Figure 4).
Wilson’s Disease 443
Figure 4. Liver histology (rhodamine staining for copper) in a WD patient.
Neurology and MRI of the CNS
Neurologic symptoms in WD include Parkinson’s-like abnormalities with rigidity,
tremor and dysarthria. In more severely affected patients there may be muscle
spasms, contractures, dysphonia, and dysphagia. In patients with pronounced
neurological symptoms magnetic resonance imaging (MRI) often identifies
abnormalities in basal ganglia such as hyperintensity on T2 weighted imaging
(Aisen 1995, van Wassanaer 1996). MRI of the CNS is superior to computed
tomography to diagnose WD.
Genetic Studies
The use of mutation analysis in WD is limited by the fact that more than 200
ATP7B mutations have been described (see
www.medgen.med.ualberta.ca/database.html). When the mutation is known in a
specific patient, gene analysis may be useful for family screening or prenatal
analysis (Thomas 1995, Shab 1997, Loudianos 1994). Some populations in Eastern
Europe show predominance of the H1069Q mutation (for literature see Roberts
2003).
Treatment
Before 1948, all patients with Wilson’s Disease died shortly after diagnosis. In
1948, intramuscular administration of the copper chelator BAL (dimercaprol) was
introduced as the first treatment of WD (Cumming 1951, Denny-Brown 1951)
followed by the oral chelators penicillamine (1955), trientine (1969) and
tetrathiomolybdate (1984). Other treatment modalities include oral zinc salts (1961)
and liver transplantation (1982). Today, most patients with WD remain on a lifelong
444 Hepatology 2012
pharmacologic therapy usually including a copper chelator and/or a zinc salt (Figure
5). LTX is reserved for fulminant liver failure and irreversible decompensation of
liver cirrhosis. Patients with a successful LTX do not need WD treatment because
LTX heals the biochemical defect. Today, most doctors use oral chelators for initial
treatment of symptomatic patients; many physicians start therapy with penicillamine
while some prefer trientine. Both drugs are probably equally effective, with trientine
having fewer side effects. In patients with advanced neurological disease some
authors recommend tetrathiomolybdate for primary therapy. Combination therapy of
chelators and zinc salts might have additive effects, acting on both urinary copper
excretion and its intestinal absorption. After removal of most accumulated copper
and regression of the most severe clinical problems the chelator dose may be
reduced and later replaced by zinc. Patients presenting without symptoms may be
treated with a rather low dose of a chelator or with a zinc salt from the beginning.
Compliance problems have been shown to regularly cause recurrence of
symptomatic WD and may lead to fulminant liver failure, need for LTX or death.
Table 1. Treatment options in WD.
Penicillamine (600-1800 mg/day)
In case of intolerance to penicillamine:
Trientine (900-2400 mg/day)
For combination of maintenance:
Zinc acetate/sulfate
For neurologic disease − not yet approved:
Tetrathiomolybdate
In acute liver failure/decompensated cirrhosis:
Liver transplantation
Restriction of food with high copper content
(does not substitute for chelators or zinc!)
Penicillamine. Penicillamine was the first oral copper chelator shown to be
effective in WD (Walshe 1955). Total bioavailability of oral penicillamine ranges
between 40 and 70% (Bergstrom 1981). Many studies have shown that
penicillamine reduces copper accumulation and provides clinical benefit in WD
(Walshe 1973, Grand 1975, Sternlieb 1980). Signs of liver disease often regress
during the initial 6 months of treatment. Non-compliance has been shown to cause
progression of liver disease, liver failure, death and LTX (Scheinberg 1987).
However, neurological symptoms may deteriorate at the start of penicillamine
treatment; it remains controversial how often this neurological deterioration occurs
and whether it is reversible; the rate of neurological worsening ranges from 10-50%
in different cohorts (Brewer1987, Walshe 1993). Some authors even recommend
not using penicillamine at all in WD patients with neurological disease (Brewer
2006). Penicillamine is associated with many side effects that lead to its
discontinuation in up to 30% of patients (for literature see Roberts 2003). An early
sensitivity reaction may occur during the first 3 weeks including fever, cutaneous
exanthema, lymphadenopathy, neutropenia, thrombocytopenia, and proteinuria. In
such early sensitivity, penicillamine should be replaced by trientine immediately.
Nephrotoxicity is another frequent side effect of penicillamine, which occurs later
Wilson’s Disease 445
and includes proteinuria and signs of tubular damage. In this case penicillamine
should be immediately discontinued. Penicillamine may also cause a lupus-like
syndrome with hematuria, proteinuria, positive antinuclear antibody, and
Goodpasture’s Syndrome. More rarely the drug can damage the bone marrow
leading to thrombocytopenia or total aplasia. Dermatologic side effects include
elastosis perforans serpiginosa, pemphigoid lesions, lichen planus, and aphthous
stomatitis. There have also been reports of myasthenia gravis, polymyositis, loss of
taste, reduction of IgA, and serous retinitis due to administration of penicillamine.
In order to minimize its side effects pencillamine should be started at 250 mg
daily; the dose may be increased in 250 mg steps every week to a maximal daily
amount of 1000 to 1500 mg given in 2 to 4 divided doses daily (Roberts 2003).
Maintenance doses range from 750 to 1000 mg/d given as 2 divided doses. In
children the dose is 20 mg/kg/d given in 2 or 3 divided doses. Penicillamine should
be given 1 hour before or 2 hours after meals because food may inhibit its
absorption. After starting penicillamine therapy serum ceruloplasmin at first may
decrease. Treatment success is checked by measuring 24-hr urinary copper that
should range between 200-500 µg/day. In the long run ceruloplasmin should
increase and free copper should regress towards normal with penicillamine therapy
(Roberts 2003).
Trientine (triene). The chemical structure of the copper chelator trientine
(triethylene tetramine dihydrochloride, short name triene) differs from
penicillamine. Trientine has usually been used as an alternative or substitute for
penicillamine, in particular when penicillamine’s major side effects are not tolerable
(Walshe 1982). Triene only rarely has side effects. Similar to penicillamine long-term treatment with trientine may cause hepatic iron accumulation in persons with
WD. Trientine is poorly absorbed from the gastrointestinal tract, and only 1%
appears in the urine (Walshe 1982). Doses range from 750 to 1500 mg/d given in 2
or 3 divided doses; 750 or 1000 mg are given for maintenance therapy (Roberts
2003). In children a dose of 20 mg/kg/d is recommended. Similar to penicillamine,
trientine should be given 1 hour before or 2 hours after meals. The effectiveness of
copper chelation by triene is measured as described for penicillamine. Triene
chelates several metals such as copper, zinc, and iron by urinary excretion and it
effectively removes accumulated copper from various organs in persons with WD as
well as in severe liver disease (Walshe 1979, Scheinberg 1987, Santos 1996, Saito
1991). It is still unclear whether penicillamine is a more effective copper chelator
when compared to triene; probably the difference in effectiveness is small (Walshe
1973, Sarkar 1977). Potential deterioration of neurological disease may also be seen
after starting triene therapy; the worsening however is less frequent and less
pronounced than that seen after starting with penicillamine.
Zinc. Most physicians substitute penicillamine or triene with zinc for
maintenance therapy when most copper accumulation has been removed. Zinc can
also be given as initial therapy in asymptomatic patients diagnosed by family
screening. A recent report however shows that WD symptoms may occur despite
zinc prophylaxis in asymptomatic patients (Mishra 2008). In a recent study from
India, 45 WD patients were on both penicillamine and zinc sulfate. The majority of
patients (84%) had neuropsychiatric manifestations. The mean duration of treatment
with penicillamine and zinc, before stopping penicillamine, was 107 months. All
patients had to stop penicillamine due to the financial burden. The patients then only
446 Hepatology 2012
received zinc sulfate for 27 months and 44 of the 45 patients (98%) remained stable.
Only one patient reported worsening in dysarthria (Sinha 2008). Zinc does not act as
an iron chelator but inhibits intestinal copper absorption and has also been
suggested to bind free toxic copper (Brewer 1983, Schilksky 1989, Hill 1987). Zinc
rarely has any side effects. It is still unclear whether zinc as monotherapy is an
effective “decoppering” agent in symptomatic patients. There are some hints that
hepatic copper may accumulate despite zinc therapy including reports about hepatic
deterioration with a fatal outcome (Lang 1993, Walshe 1995). Therefore some
authors use zinc in combination with a chelator. Neurological deterioration is rather
rare under zinc therapy (Brewer 1987, Czlonkowska 1996). The recommended
doses of zinc vary in the literature: according to AASLD practice guidelines dosing
is in milligrams of elemental zinc (Roberts 2003). For larger children and adults,
150 mg/d is administered in 3 divided doses. Compliance with doses given thrice
daily may be problematic; zinc has to be taken at least twice daily to be effective
(Brewer 1998). Other authors recommend using zinc sulfate at 150 mg thrice daily
as a loading dose and 100 mg thrice daily for maintenance. Further
recommendations suggest giving 50 mg as zinc acetate thrice daily in adults. The
type of zinc salt used has been thought to make no difference with respect to
efficacy (Roberts 2003). However, zinc acetate has been suggested to cause the least
gastrointestinal discomfort. When zinc is combined with a chelator the substances
should be given at widely spaced intervals, potentially causing compliance
problems. Effectiveness of the zinc treatment should be checked as described for
penicillamine and zinc (Roberts 2003).
Tetrathiomolybdate. Tetrathiomolybdate is an experimental copper chelator not
approved by FDA or EMA. It has been suggested as the initial treatment of WD
patients with neurological involvement. Early reports say that tetrathiomolybdate
stabilizes the neurological disease and reduces circulating free copper in a matter of
weeks (Brewer 1994, Brewer 1996). A more recent randomized study supports this
view and also suggests that zinc monotherapy is insufficient for treatment of
neurological WD (Brewer 2006).
Vitamin E, other antioxidants and diet. Since serum and hepatic concentrations
of vitamin E levels may be reduced in WD (von Herbay 1994, Sokol 1994) it has
been suggested to complement vitamin E intake. Some authors have also
recommended taking other antioxidants; studies have not proven their effectiveness
as yet.
WD patients should avoid food with high copper content (nuts, chocolate,
shellfish, mushrooms, organ meats, etc). Patients living in older buildings should
also check whether the water runs through copper pipes. Such dietary and lifestyle
restrictions do not replace chelator or zinc therapy (Roberts 2003).
Fulminant hepatic failure and LTX. Most WD patients with fulminant liver
failure need LTX urgently in order to survive (Sokol 1985, Roberts 2003).
However, in a long-term cohort study only two patients died prior to LTX being
available (Stremmel 1991). It is a difficult clinical question whether WD patients
with liver failure can survive without LTX. The prognostic score used to help with
this difficult decision includes bilirubin, AST, and INR (Nazer 1986). In any case,
WD patients with signs of fulminant liver failure need to be transferred immediately
(same day!) to a transplant center.
Wilson’s Disease 447
WD patients with a chronic course of decompensated cirrhosis follow the usual
rules for LTX. LTX cures the metabolic defects and thus copper metabolism returns
to normal afterwards (Groth 1973). Prognosis for WD after LTX is excellent, in
particular when patients survive the first year (Eghtesad 1999). It is still unclear
under which circumstances LTX may be helpful for WD patients with neurological
complications, which do not respond to drug therapy. In some patients CNS
symptoms regress after LTX while other patients do not improve (for literature see
Brewer 2000).
Asymptomatic Patients. All asymptomatic WD subjects - usually identified by
family screening - need to be treated by chelators or zinc in order to prevent life-threatening complications (Walshe 1988, Brewer 1989, Roberts 2003). It is unclear
whether therapy should begin in children under the age of 3 years.
Maintenance Therapy. After initial removal of excessive copper by chelators,
some centres replace the chelators with zinc for maintenance therapy. It is unclear
when such change is advisable and whether it might be better to reduce the dose of
chelators instead of replacing them with zinc. It is generally accepted that
replacement of chelators with zinc should only be done in patients who are
clinically stable for some years, have normal aminotransferase and liver function, a
normal free copper concentration and a 24-hr urinary copper repeatedly in the range
of 200-500 µg while on chelators (Roberts 2003). Long-term treatment with zinc
may be associated with fewer side effects than chelator treatment. Many patients on
trientine, however, do have significant side effects, and this author believes one
does need to replace trientine with zinc in such patients. In any case, therapy either
with a chelator or with zinc needs to be maintained indefinitely; any interruption
may lead to lethal liver failure (Walshe 1986, Scheinberg 1987).
Pregnancy. Treatment must be maintained during pregnancy because an
interruption has been shown to carry a high risk of fulminant liver failure (Shimono
1991). Maintenance therapy with chelators (penicillamine, trientine) or with zinc
usually results in a good outcome for mother and child, although birth defects have
(rarely) been documented [for literature see Sternlieb 2000). It is recommended that
the doses of both chelators be reduced, if possible by about 50%, in particular
during the last trimester to avoid potential problems in wound healing (Roberts
2003). Zinc does not need to be reduced.
Monitoring of treatment
Monitoring should be done closely during initial treatment in all WD patients to
look for efficacy (Figure 6) and side effects. During the maintenance phase patients
should be checked at least twice a year.
Table 2. Monitoring the treatment efficacy in WD.
Clinical Improvement (Neurologic features, liver disease, hematology)
Regression of Kayser-Fleischer Ring
Circulating free copper <10 µl/dl
24-hr urinary copper excretion (200-500 µg/day on chelators)
Decrease in liver copper content
448 Hepatology 2012
Clinical examinations include neurological, ophthalmologic and psychiatric
consultations (Figure 7). Patients with liver involvement need to be checked
carefully for signs of liver failure.
Laboratory tests include measurements of serum copper and ceruloplasmin,
calculation of free (nonceruloplasmin-bound) copper (see above), and 24-hr urinary
copper excretion (Roberts 2003). While on chelating therapy 24-hr urinary copper
excretion should initially range between 200 and 500 µg; such a value can also
suggest that the patient is adherent to the drug. After removal of copper
accumulation, urinary copper excretion may be lower. Prognosis of WD is
dependent on the initial severity of the disease and then on adherence to the life-long treatment. Patients treated prior to severe and potentially irreversible
neurological and hepatic complications have a good prognosis approaching a
normal life expectancy (Figure 8). Irreversible liver disease often can be treated
successfully by LTX while some patients with severe neurological disease do not
get better despite optimal therapy.
Figure 5. Findings prior to and after beginning chelating therapy in
53 WD patients (modified from Stremmel 1991).
Figure 6. Cumulative survival in 51 WD patients versus a matched
general population (modified from Stremmel 1991).
Wilson’s Disease 449
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