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Aliment Pharmacol Ther 2004; 19: 157–165.
doi: 10.1046/j.1365-2036.2003.01813.x
Review article: diagnosis and current therapy of Wilson’s disease
P. FEREN CI
Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria
Accepted for publication 14 October 2003
SUMMARY
Wilson’s disease is an autosomal recessive inherited
disorder of hepatic copper metabolism resulting in liver
disease and/or neuropsychiatric disease. The diagnosis
of neurological disease is straightforward if the following symptoms are present: Kayser–Fleischer rings,
typical neurological symptoms and low serum ceruloplasmin levels. The diagnosis is more complex in
patients presenting with liver diseases. None of the
commonly used parameters alone allows a diagnosis
with certainty. A combination of various laboratory
parameters is necessary to firmly establish the diagno-
INTRODUCTION
Wilson’s disease is an autosomal recessive inherited
disorder of hepatic copper metabolism resulting in the
accumulation of copper in many organs and tissues.
The hallmarks of the disease are the presence of liver
disease, neurological symptoms and Kayser–Fleischer
corneal rings.
Copper is an essential dietary nutrient and is needed
for such diverse processes as mitochondrial respiration,
melanin biosynthesis, dopamine metabolism, iron
homeostasis, antioxidant defence, connective tissue
formation and peptide amidation. Specific pathways
allow the intracellular trafficking and compartmentalization of copper, ensuring adequate cuproprotein
synthesis whilst avoiding cellular toxicity. Biliary excreCorrespondence to: Professor P. Ferenci, Department of Internal Medicine
IV, Gastroenterology and Hepatology, University of Vienna, Währinger
Gürtel 18–20, A1090 Vienna, Austria.
E-mail: [email protected]
Ó 2003 Blackwell Publishing Ltd
sis. In the future, limited mutation analysis may play
an important diagnostic role. Recently, a group of
international experts has proposed a score based on a
variety of tests and clinical symptoms. The validity of
this score needs to be assessed prospectively. Treatment requires life-long administration of copper chelators (d-penicillamine, trientine). A frequently used
alternative is zinc. None of these treatments has been
tested by prospective randomized controlled studies.
Liver transplantation is reserved for severe or treatment-resistant cases with advanced liver disease,
whilst experience with refractory neuropsychiatric
disease is limited.
tion is the only mechanism for copper elimination, and
the amount of copper excreted in the bile is directly
proportional to the size of the hepatic copper pool.
Trafficking of copper in the hepatocytes is complex and
involves several transport proteins. The copper transporter 1 transports copper with high affinity in a metalspecific, saturable fashion at the hepatocyte plasma
membrane.1, 2 Metallothioneins, a group of cysteinerich intracellular proteins capable of binding metal ions,
including copper, cadmium and zinc,3 have a critical
role in protecting intracellular proteins from copper
toxicity.4 Metallochaperones transfer copper to the site
of synthesis of copper-containing proteins.5, 6 The
cytoplasmic copper chaperone atox1 is required for
copper delivery to the Wilson ATPase (ATP7B) in the
hepatocyte secretory pathway7 by direct protein–protein interaction.7–9 In the copper-limiting environment
of the cell, the delivery of copper by atox1 is responsible
for initiating the catalytic activity and the intracellular
trafficking of ATP7B.10 ATP7B is the gene product of
157
158
P. FERENCI
the Wilson’s disease gene (see Figure 1) located on
chromosome 13 and is a polytopic membrane protein
containing several motifs characteristic of P-type ATPases.11 The histidine residue in the SEHPL motif within
the cytoplasmic loop is the site of the H1069Q missense
mutation, a common disease allele found in northern,
central and eastern European populations with Wilson’s
disease.12–15 In hepatocytes, this ATPase resides in the
trans-Golgi network transporting copper into the secretory pathway for incorporation into apoceruloplasmin
and excretion into the bile16 (see Figure 2). Molecular
genetic analysis of affected patients reveals over 200
distinct mutations (database maintained at the University of Alberta (http://www.medgen.med.ualberta.ca)).
About one-half of these mutations are missense, with
most confined to recognized consensus motifs or
predicted transmembrane domains. A detailed review
of hepatic copper transport has recently been published.17
CLINICAL PRESENTATIONS
Wilson’s disease may present with a variety of clinical
conditions, the most common being liver disease and
neuropsychiatric disturbances. None of the clinical signs
is typical or diagnostic. One of the most characteristic
features of Wilson’s disease is that no two patients, even
within a family, are ever quite alike. With the increased
awareness of Wilson’s disease, patients are being diagnosed earlier and ‘late’ consequences of the disease, such
as Kayser–Fleischer rings or severe neurological symptoms, can be prevented and, in future, may occur less
frequently. Uncommon manifestations of Wilson’s
disease include hypercalciuria and nephrocalcinosis,
Figure 2. Roles of the Wilson ATPase (ATP7B) in hepatic copper
transport. CPL, ceruloplasmin; CTR1, copper transporter 1; MT,
metallothionein.
chondrocalcinosis and osteoarthritis, sunflower cataracts
and cardiac manifestations.
The finding of a Kayser–Fleischer ring is a useful
indicator of severe copper overload. If the ring is not
detected by clinical inspection, the cornea should be
examined under a slit lamp by an experienced ophthalmologist. Kayser–Fleischer rings are present in 95% of
patients with neurological symptoms, in 50–60% of
patients without neurological symptoms and in only
10% of asymptomatic siblings.
Most patients with Wilson’s disease, whatever their
clinical presentation or pre-symptomatic status, have
some degree of liver disease. The most common age of
hepatic manifestation is between 8 and 18 years;
however, cirrhosis may be present in children below
the age of 5 years, or may be diagnosed in patients
presenting with advanced chronic liver disease in their
fifties or sixties, without neurological symptoms and
without Kayser–Fleischer rings. Liver disease may
mimic all forms of common liver conditions, including
asymptomatic transaminasaemia, acute or chronic
hepatitis, fulminant hepatic failure and cirrhosis.
Acute Wilsonian hepatitis and fulminant Wilson’s disease
Figure 1. Schematic presentation of the Wilson ATPase (ATP7B).
Acute Wilsonian hepatitis is indistinguishable from
other forms of acute (viral or toxic) liver diseases.
Kayser–Fleischer rings and neurological abnormalities
may be absent in most patients. The disease may rapidly
deteriorate and resemble fulminant hepatic failure.
Large amounts of stored copper are released from
necrotic hepatocytes and induce a severe haemolytic
anaemia complicating acute liver disease. Although
Wilson’s disease is rare, it accounts for 6–12% of
patients with fulminant hepatic failure referred for
emergency liver transplantation. Rapid diagnosis may
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
REVIEW: DIAGNOSIS AND THERAPY OF WILSON’S DISEASE
be very difficult. Serum aminotransferase activity is
usually less than 10 times normal and thus is much
lower than the values commonly recorded in fulminant hepatitis of other aetiologies. The combination of
anaemia, marked jaundice and relatively low aminotransferase activities in young patients should always
raise the suspicion of acute Wilson’s disease.18, 19 An
alkaline phosphatase to total bilirubin ratio below 2.0
has been claimed to provide 100% sensitivity and
specificity for the diagnosis of Wilsonian fulminant liver
failure, but this was not confirmed in larger series. The
best diagnostic test is the quantification of copper in
biopsy material or in the explanted liver. One puzzling
feature of fulminant Wilson’s disease is the preponderance of females (female to male ratio, 3 : 1).
Chronic hepatitis and cirrhosis due to Wilson’s disease
Wilson’s disease may present with a clinical syndrome
indistinguishable from chronic hepatitis or cirrhosis of
other aetiology.20 Liver biopsy shows chronic hepatitis
or advanced cirrhosis, but the diagnosis may be missed
if the hepatic copper content is not measured. Without
treatment, patients progressively deteriorate and may
die of liver failure.
Neuropsychiatric disease
Neurological symptoms usually develop in the midteenage years or twenties.21 However, there are welldocumented cases of late (45–55 years) neurological
disease. The initial symptoms may be very subtle, such
as mild tremor and speech and writing problems, and
are frequently misdiagnosed as behavioural problems
associated with puberty. The hallmark of neurological
Wilson’s disease is a progressive movement disorder
characterized by dysarthria, dysphagia, apraxia and a
tremor–rigidity syndrome (‘juvenile Parkinsonism’).
About one-third of patients present with psychiatric
abnormalities, such as reduced performance in school
or at work, depression, labile mood, sexual exhibitionism and frank psychosis. Frequently, adolescents with
problems in school or work are referred for psychological counselling and psychotherapy.
Patients presenting with neurological symptoms may
also suffer from significant liver disease. In a substantial
proportion, symptomatic liver disease pre-dates the
occurrence of neurological signs. In many patients with
neurological disturbances, asymptomatic liver disease
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
159
can only be diagnosed by liver biopsy.22 However, if a
liver biopsy is performed in all patients presenting with
neurological symptoms at diagnosis, the proportion of
patients with cirrhosis is 38.7%23 and about one-half of
patients have only minimal liver disease.
DIAGNOSIS
The diagnosis of neurological Wilson’s disease is usually
made on the basis of clinical findings and laboratory
abnormalities (see Table 1). No additional tests are
required if Kayser–Fleischer rings are present and/or
serum ceruloplasmin levels are low.24 However, there
are a few well-documented cases of neurological
Wilson’s disease without Kayser–Fleischer rings.25
Clinical neurological examination is more sensitive
than any other method for the detection of neurological
abnormalities. Brain magnetic resonance imaging is
useful for documenting the extent of changes in the
central nervous system.26 The most common abnormalities are changes in the signal intensity of grey and
white matter and atrophy of the caudate nucleus,
brainstem and cerebral and cerebellar hemispheres.
The diagnosis is more complex in patients presenting
with liver diseases (see Figure 3). None of the commonly used parameters alone allows a certain diagnosis
of Wilson’s disease. Usually, a combination of various
laboratory parameters is necessary to firmly establish
the diagnosis. Kayser–Fleischer rings may be absent in
up to 50% of patients with Wilsonian liver disease and
in an even higher proportion with fulminant Wilson’s
disease. Serum ceruloplasmin may be in the low to
normal range in up to 45% of patients with hepatic
Wilson’s disease.27 On the other hand, even a low
ceruloplasmin level is not diagnostic for Wilson’s disease
in the absence of Kayser–Fleischer rings. Ceruloplasmin
can be decreased in severely malnourished subjects and
in heterozygous carriers of the Wilson’s disease gene.28
Very low levels were found in a patient with autoimmune hepatitis, which increased following steroid
treatment. Ceruloplasmin is undetectable in familial
aceruloplasminaemia. Thus, in patients with liver
disease, a normal ceruloplasmin level cannot exclude
Wilson’s disease, nor is a low level sufficient to make a
diagnosis of Wilson’s disease. Ceruloplasmin is an acute
phase reactant and its serum concentration increases as
a consequence of inflammation. Most patients with
marked liver disease have normal ceruloplasmin levels.
An over-estimation of serum ceruloplasmin can be
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P. FERENCI
Table 1. Routine tests for the diagnosis of Wilson’s disease
Test
Typical finding
False ‘negative’
False ‘positive’
Serum ceruloplasmin
Decreased
24-h urinary copper
> 100 lg/day
Low levels in:
malabsorption
aceruloplasminaemia
liver insufficiency
heterozygotes
Increased:
hepatocellular necrosis
contamination
Serum ‘free’ copper
> 10 lg/dL
Hepatic copper
> 250 lg/g dry weight
Kayser–Fleischer
rings by slit lamp
Present
Normal levels in
patients with marked
hepatic inflammation
Over-estimation by
immunological assay
Normal:
incorrect collection
children without liver disease
Normal if ceruloplasmin
over-estimated by
immunological assay
Due to regional variation:
in patients with active liver disease
in patients with regenerative nodules
In up to 40% of patients with
hepatic Wilson’s disease
In most asymptomatic siblings
Cholestatic syndromes
Primary biliary cirrhosis
Figure 3. An algorithm for the diagnosis of
Wilson’s disease. CPL, ceruloplasmin; KFR,
Kayser–Fleischer rings. *Depends on availability. In Europe: H1069Q, exons 8 and
15. àEither at baseline or after d-penicillamine challenge.
suspected if the serum copper concentration is lower
than expected from the measured ceruloplasmin level
(which contains 0.3% of copper). The ‘free’ copper
concentration can be calculated by subtracting from the
total copper concentration the ceruloplasmin-bound
copper (ceruloplasmin times 3.3). An increased ‘free’
copper is not useful diagnostically, but can be employed
as an adjunct to diagnosis, and is more important for
monitoring the response to treatment.
Urinary copper excretion is increased in patients with
Wilson’s disease; however, its usefulness in clinical
practice is limited. The estimation of urinary copper
excretion may be misleading due to the incorrect
collection of the 24-h urinary volume or to copper
contamination. In pre-symptomatic patients, urinary
copper excretion may be normal, but increases after
d-penicillamine challenge.29 However, urinary copper
excretion is also increased in any disease with extensive
hepatocellular necrosis.
The hepatic copper content is increased in 82% of
patients with Wilson’s disease and usually exceeds
250 lg/g dry weight (normal, up to 50 lg/g dry
weight). In the absence of other tests suggestive of
abnormal copper metabolism, a diagnosis of Wilson’s
disease cannot be made on the basis of an increased
hepatic copper content alone. Patients with chronic
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
REVIEW: DIAGNOSIS AND THERAPY OF WILSON’S DISEASE
cholestatic diseases, neonates and young children and
possibly also subjects with exogenous copper overload
have increased hepatic copper concentration of
> 250 lg/g dry weight. In a recent study, we measured
the hepatic copper content in 103 liver biopsies
obtained at the diagnosis of Wilson’s disease, in
212 patients with a variety of non-cholestatic liver
diseases (including 144 with chronic hepatitis C and 44
with non-alcoholic fatty liver disease), in 27 patients
with chronic cholestasis and in 26 patients without
evidence of liver disease.23 The liver copper content was
> 250 lg/g dry weight in 85 (81%) Wilson’s disease
patients, between 50 and 250 lg/g dry weight in
15 and in the normal range in four. The liver copper
content did not correlate with age, grade of fibrosis or
presence of stainable copper. The liver copper content
was > 250 lg/g dry weight or between 50 and
250 lg/g dry weight in three (1.4%) and 20 (9.1%) of
the 219 patients with non-cholestatic liver diseases,
respectively. By lowering the cut-off from > 250 to
75 lg/g dry weight, the sensitivity of liver copper content
for the diagnosis of Wilson’s disease increased from
81.2% to 96%, the negative predictive value increased
from 88.2% to 97.1%, but the specificity (98.6% to
90.1%) and the positive predictive value (97.6% to
87.4%) decreased. It was concluded that, although liver
copper content is a useful parameter, it neither proves or
excludes Wilson’s disease with certainty. The diagnosis
requires a combination of a variety of clinical and
biochemical tests. Recently, a group of international
experts has discussed this issue and has proposed a score
based on a variety of tests and clinical symptoms.30 The
validity of this score needs to be assessed prospectively.
Liver biopsy findings are generally non-specific and are
not helpful for the diagnosis of Wilson’s disease;
however, the exclusion of other aetiologies may be
equally important and may require a liver biopsy. The
pathology includes early changes, such as fatty intracellular accumulations, which often proceed to marked
steatosis. At later stages, portal and periportal lymphocytic infiltrates and the presence of necrosis and
fibrosis may be indistinguishable from other forms of
hepatitis. Some patients have cirrhosis without any
inflammation. The detection of focal copper stores by
the rhodanine stain is a pathognomonic feature of
Wilson’s disease, but is only present in a minority
(about 10%) of patients.31
The ultrastructural abnormalities include changes in
mitochondria and peroxisomes and are stage specific.
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
161
Molecular genetic testing
Mutation analysis for diagnosis is cumbersome because
of the occurrence of many mutations, each of which is
rare. Furthermore, most patients are compound heterozygotes (i.e. carry two different mutations). Direct
mutation analysis for diagnosis is only helpful if a
mutation occurs with a reasonable frequency in the
population. In northern, central and eastern Europe,12, 14, 15 the most common mutations are: H1069Q
mutation (allele frequency, 43.5%), mutations of exon 8
(6.8%), 3400delC (3%) and P969Q (1.6%).32 In other
parts of the world, the pattern of mutations is different
(Turkey, A1003T and P969Q;33 Sardinia, UTR -441/427del, 2463delC;34 Far East, R778L35, 36). Eventually,
a multiplex polymerase chain reaction for the most
frequent Wilson’s disease mutations in the region
should make direct mutation analysis for diagnosis
feasible and obtainable within a week.
Family screening
Once a diagnosis of Wilson’s disease is made in an index
patient, an evaluation of his or her family is mandatory.
The likelihood of finding a homozygote amongst the
siblings is 25% and amongst the children 0.5%. Testing
of second-degree relatives is only useful if the gene is
found in one of the immediate members of the relative’s
family. No single test is able to identify affected siblings
or heterozygote carriers of the Wilson’s disease gene
with sufficient certainty.37 Today, mutation analysis is
the only reliable tool for screening the family of an index
case with known mutations; otherwise haplotype
analysis can be used. A number of highly polymorphic
microsatellite markers that closely flank the gene allow
the Wilson’s disease gene to be traced in a family.38 For
such an analysis, at least one first-degree relative and
the index patient are required.
TREATMENT
Treatments for Wilson’s disease have progressed from
the intramuscular administration of dimercaprol (BAL)
to the more easily administered oral penicillamine.
Alternative agents to penicillamine, such as trientine,
have been developed and introduced specifically for
patients with adverse reactions to penicillamine. Zinc
was developed separately, as was tetrathiomolybdate,
which was used for copper poisoning in animals.
162
P. FERENCI
Today, the mainstay of treatment for Wilson’s disease
remains life-long pharmacological therapy, but the
choice of drug mostly depends on the opinion of the
treating physician and is not based on comparative
data.
According to the recent AASLD practice guidelines on
Wilson’s disease, initial treatment for symptomatic
patients should include a chelating agent (penicillamine
or trientine).39 Treatment of pre-symptomatic patients
and maintenance therapy of successfully treated symptomatic patients can be accomplished with the chelating
agents penicillamine or trientine, or with zinc.39 Liver
transplantation, which corrects the underlying hepatic
defect in Wilson’s disease, is reserved for severe or
resistant cases.
Penicillamine
Penicillamine is still the ‘gold standard’ for therapy.40
Penicillamine reduces copper bound to protein and
thereby decreases the affinity of the protein for
copper. Reduction of copper facilitates its binding to
the drug. The copper mobilized by penicillamine is
then excreted in the urine. Most symptomatic patients,
whether hepatic, neurological or psychiatric, respond
within months of starting treatment. Amongst neurological patients, a significant number may experience an initial worsening of symptoms before they get
better.
The usual dose of penicillamine is 1–1.5 g/day. Once
the clinical benefit has been established, it is possible to
reduce the dosage to 0.5–1 g/day. Initially, this dose
will cause a large cupriuresis, but copper excretion later
decreases to 0.5 mg/day. To prevent deficiency induced
by penicillamine, pyridoxine (vitamin B6) should be
supplemented (50 mg/week). A major problem of penicillamine is its high level of toxicity. In our series, 20%
of patients had major side-effects and were switched to
other treatments. Others report even higher frequencies
of side-effects. There are two broad classes of penicillamine toxicity: direct, dose-dependent side-effects and
immunologically induced lesions. Direct side-effects
include pyridoxine deficiency and interference with
collagen and elastin formation. The latter results in
skin lesions such as cutis laxa and elastosis perforans
serpingiosa. Immunologically mediated side-effects include leucopenia and thrombocytopenia, systemic lupus
erythematodes, immune complex nephritis, pemphigus,
buccal ulcerations, myasthenia gravis, optic neuritis
and Goodpasture syndrome. Immunologically mediated
side-effects require the immediate cessation of penicillamine.
Trientine
Trientine is a copper chelator, acting primarily by
enhancing urinary copper excretion. Trientine is
licensed for the treatment of Wilson’s disease and is
as effective as penicillamine with far fewer sideeffects.41 However, the efficacy of trientine has not
been compared with penicillamine as an initial treatment of Wilson’s disease. Anecdotal reports and our
own experience indicate that trientine is a satisfactory
first-line treatment for Wilson’s disease. Trientine
appears to be more potent than penicillamine in the
mobilization of copper, but cupriuresis diminishes more
rapidly than with penicillamine. The cupriuretic power
of trientine, however, is sufficient to keep the patient
clinically well.
Ammonium tetrathiomolybdate
This drug has two mechanisms of action. First, it
complexes with copper in the intestinal tract and
thereby prevents the absorption of copper. Second, the
absorbed drug forms a complex with copper and
albumin in the blood and renders the copper unavailable for cellular uptake. The experience with this drug is
very limited, but it appears to be useful for the initial
treatment of patients with neurological symptoms.42
Zinc
Zinc interferes with the intestinal absorption of copper
by two mechanisms. Both metals share the same
carrier in enterocytes and pre-treatment with zinc
blocks this carrier for copper transport (with a half-life
of about 11 days).43 The impact of the zinc-induced
blockade of copper transport by other carriers into the
enterocytes has not been studied. Second, zinc induces
metallothionein in enterocytes, which acts as an
intracellular ligand binding metals,44 which are then
excreted in the faeces with desquamated epithelial
cells. Indeed, the faecal excretion of copper is increased
in patients with Wilson’s disease on treatment with
zinc. Furthermore, zinc also induces metallothionein in
the liver, protecting hepatocytes against copper
toxicity.45
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
REVIEW: DIAGNOSIS AND THERAPY OF WILSON’S DISEASE
Data on zinc in the treatment of Wilson’s disease have
been derived from uncontrolled studies using different
zinc preparations (zinc sulphate, zinc acetate) at different doses (75–250 mg/day).46 The efficacy of zinc has
been assessed by four different approaches. First,
patients successfully decoppered by d-penicillamine
were switched to zinc and the maintenance of their
asymptomatic condition was monitored. Most patients
maintained a negative copper balance and no symptomatic recurrences occurred. Some patients, however,
died of liver failure after treatment was switched to zinc.
Brewer et al. observed the occurrence of severe neurological symptoms in a 25-year-old asymptomatic
sibling 4 months after switching from d-penicillamine
to zinc.47
A second group includes symptomatic patients
switched to zinc as an alternative treatment due to
intolerance to d-penicillamine. 16 case histories have
been published so far. Liver function and neurological
symptoms improved in three and five patients, respectively. One patient further deteriorated neurologically
and improved on re-treatment with d-penicillamine.
The remaining patients remained in a stable condition.
Follow-up studies in 141 patients have demonstrated
that zinc is effective as sole therapy in the long-term
maintenance treatment of Wilson’s disease.47
In a third group, zinc was used as first-line therapy.48
About one-third of patients were asymptomatic siblings
of patients with Wilson’s disease and two-thirds presented with neurological or hepatic symptoms. Most
patients remained free of symptoms or improved. In
15%, neurological symptoms worsened and improved
on d-penicillamine. Three patients died of progressive
liver disease.
Finally, in a prospective study, in 67 newly diagnosed
cases of Wilson’s disease, the efficacies of d-penicillamine and zinc were similar.49 Zinc was better tolerated
than d-penicillamine. However, two zinc-treated patients
died of progressive liver disease.
Antioxidants
Antioxidants, mainly vitamin E, may have a role as
adjunctive treatment. Serum and hepatic vitamin E
levels have been found to be low in Wilson’s
disease.50 Symptomatic improvement when vitamin
E is added to the treatment regimen has been reported
occasionally, but no rigorous studies have been
conducted.
Ó 2003 Blackwell Publishing Ltd, Aliment Pharmacol Ther 19, 157–165
163
Monitoring therapy
If a decoppering agent is used for treatment, compliance
can be tested by repeated measurement of the 24-h
urinary copper excretion. This approach is not useful if
patients are treated with zinc. If, in a compliant patient,
urinary copper excretion decreases over time and
stabilizes at < 500 lg/day, the dose of d-penicillamine
can be lowered.
The efficacy of treatment can be monitored by the
determination of ‘free’ copper in serum and, depending
on the presenting symptoms, liver disease can be
assessed by routine liver function tests; repeated liver
biopsies with measurement of hepatic copper content
are not helpful. Improvement of neurological symptoms
can be documented by clinical examination. In addition,
some of the magnetic resonance imaging abnormalities
are fully reversible on treatment. Auditory evoked
brainstem potentials are also helpful to document
improvement by decoppering treatment.51, 52
Liver transplantation
Liver transplantation is the treatment of choice in
patients with fulminant Wilson’s disease and in those
with decompensated cirrhosis. In addition to improving
survival, liver transplantation also corrects the biochemical defect underlying Wilson’s disease. However,
the role of this procedure in the management of patients
with neurological Wilson’s disease, in the absence of
hepatic insufficiency, is still uncertain.
Schilsky et al. analysed 55 transplants performed in
33 Wilson’s disease patients with decompensated
cirrhosis and in 21 patients with Wilsonian fulminant
hepatitis in the USA and Europe.53 The median
survival after orthotopic liver transplantation was
2.5 years; the longest survival time after transplantation was 20 years. Survival at 1 year was 79%. Nonfatal complications occurred in five patients. Fifty-one
orthotopic liver transplants were performed on
39 patients (16 paediatric, 23 adults) with Wilson’s
disease at the University of Pittsburgh.54 The rate of
primary graft survival was 73% and patient survival
was 79.4%. Survival was better in those with chronic
advanced liver disease (90%) than in those with
fulminant hepatic failure (73%). In the Mayo Clinic
series, the 1-year survival ranged from 79% to 87%,
with an excellent chance for survival long term.55 The
outcome of neurological disease following orthotopic
164
P. FERENCI
liver transplantation is uncertain. In a retrospective
survey, four of seven patients with neurological or
psychiatric symptoms due to Wilson’s disease improved
after orthotopic liver transplantation. Anecdotal
reports document a dramatic improvement in neurological function within 3–4 months after orthotopic
liver transplantation. In contrast, central pontine and
extrapontine myelinolysis and new extrapyramidal
symptoms developed in a patient 19 months after
orthotopic liver transplantation.56 Some patients with
psychiatric or neurological symptoms transplanted for
decompensated cirrhosis have shown improvement of
these symptoms following orthotopic liver transplantation.57
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