Living with Wilson's
> Guide to Wilson's disease
Contents are listed below,
select individual topics by clicking on title, alternatively scroll down the
page.
| What
is Wilson's disease? |
Wilson's disease
is an inherited condition in which copper is not excreted properly from the
body. The excess copper can build up in the liver and/or brain causing liver
damage and/or neurological problems. It can also collect in other parts of
the body including the eyes and the kidneys.
Copper begins to accumulate immediately after birth but the symptoms usually
appear in the 2nd to 3rd decade. The first signs are hepatic (liver) in about
40% of cases, neurological (brain) in about 35% of cases and psychiatric,
renal (kidney), haematological (blood), or endocrine (glands) in the remainder.Back to top
| What are the signs and symptoms of Wilson's disease? |
In some cases
these can be very mild, everyday symptoms such as tiredness, loss of appetite,
abdominal pain, vomiting, weight loss, nose bleeds and anaemia. These symptoms
may come and go over a period of months or even years, or they may be more
persistent. Some patients also experience kidney problems, i.e. tubular dysfunction,
which generally causes no symptoms, and joint problems, which are very rare.
In other cases the symptoms may be more acute, especially when the liver is
involved.
Liver
disease can be broadly subdivided in to:
- acute liver disease due to copper overload. In this case the
patient is likely to be severely ill and yellow. A liver transplantation
may be necessary if treatment does not quickly result in improvement
- acute hepatitis: this is more
or less the same as acute liver disease
- chronic liver disease: slow scarring of the liver due to copper
overload, which will ultimately also result in severe damage to the liver.
Some of the
kinds of neurological problems can include:
- deterioration in school performance
or handwriting
- mild tremors
- dystonia: this is a type of cramping or stiffening of the muscles.
Often this begins with muscle cramps in the arms or legs, and as the disease
progresses, it may result into pulling parts of the body more or less permanently
into abnormal postures
- ataxia: loss of the ability to
coordinate muscular movement
- muscular rigidity
- dysarthria: this is the medical term for speech abnormality. The
dysarthria in Wilson's disease can take many forms, including slurring,
low volume, a repetitive aspect in trying to pronounce certain words, and
can progress to complete inability to speak (anarthria).
About one third
of patients initially present with psychiatric abnormalities, including depression,
personality and mood changes. Back to top
| Metabolic
pathway of copper |
Copper is present in most
foods and is necessary for normal growth and development.
Diagrams I-IV show the way copper is metabolized in healthy subjects, and
in people with Wilson's disease (without treatment and with treatment). Back to top
| How have I or my child got this condition? |
Wilson's disease
is a genetic disorder. This means that it is not brought about by anything
that may have occurred during pregnancy, neither is it an infectious or contagious
disease. Genetic disorders are inherited and the pattern in which you or your
child may have developed the condition will now be described. Every person
carries more than 30000 genes, amongst which there is an estimated defect
in approximately seven genes. If by accident you and your partner both carry
the same genetic defect (in this case for Wilson's disease), with each pregnancy,
there is a one in four chance that your baby will be born with Wilson's disease.
If the gene is inherited from both mum and dad, like in Wilson's disease,
it is described as being "autosomal recessive"
The risk of being affected is the same for both girls and boys. The frequency
of Wilson's disease is very low: 1 out of 30000 to 50000 birthsBack to top
Diagram V shows
you how this happens.
| Diagram V
| |
Unaffected child - not a carrier |
| |
Unaffected child - carries the genetic fault |
| |
Child that has Wilson's disease |
| |
Unaffected child - carries the genetic fault |
In this diagram both mum and dad carry the same genetic defect
(orange triangle). Each time that mum gets pregnant, there is a one
in four chance that the child will inherit the genetic defect from
both parents and will be born with Wilson's disease. |
Back to top
| Diagnostic tests for Wilson's disease |
The diagnosis
of Wilson's disease is made by relatively simple tests. These tests can diagnose
the disease in both symptomatic patients and people who show no signs of the
disease "pre-symptomatic"
The copper
accumulation in the eye in Wilson's disease may cause a diagnostic golden-brown
ring to form around the edge of the iris, called a Kayser-Fleischer ring.
This ring is only visible using a special instrument (slit-lamp) and is rarely
present before the age of 10 years.
Listed below
are the standard laboratory tests used to diagnose Wilson's disease:
- Urine copper is high; this should
be measured in a 24 hour urine collection.
- "Caeruloplasmin", a
copper-containing protein in blood plasma is usually low.
- The copper concentration measured
in a liver biopsy specimen will be high.
- The cerebral imaging (MRI) may
be abnormal.
- In cases which are difficult
to diagnose, copper isotope studies (more complex copper tests) may be performed.
| Parameter |
Normal |
Wilson's |
| Plasma caeruloplasmin |
>200 mg/l |
<200 mg/l |
| Urine Cu |
<0.6 µmol/24 h |
>1.6 µmol/24 h |
| Hepatic copper |
< 250 µg/g dry wt |
> 250 µg/g dry wt |
| Kayser Fleischer rings |
Absent |
Present in neurological cases, but may be absent in younger
children |
| Cerebral imaging (MRI) |
Normal |
May be abnormal |
Back to top
With proper
drug therapy, disease progression can generally be halted, and usually symptoms
can even be improved. The treatment goal is to first remove the copper which
has accumulated in the body, and then prevent its re-accumulation. Therapy
must be life-long.
Treatment should be adapted to the clinical stage of the disease (pre-symptomatic
stage, hepatic presentation, neurological presentation, maintenance therapy,
and pregnancy). Patients should consult with their physician to see which
drug is most appropriate. Back to top
The expression
"good compliance" describes the fact that the medical prescription
is respected, whether it is a medical treatment, taken in correct doses and
regularly, or other prescriptions such as a diet, or respecting an appointment
with the doctor. "Poor compliance" describes medical prescriptions
that are not respected and medical treatment that is not taken regularly.
Treatment for Wilson's disease is a life-long therapy. The effectiveness and
side effects of treatment will be monitored at regular hospital follow-up
visits which include blood and urine tests. If taken correctly and continuously
(good compliance) treatment is very effective. If doses are missed regularly
or treatment stopped for a period of time (poor compliance), the liver and/or
brain may be permanently damaged before any problems are noticed. Back to top
Treatment must
be continued throughout pregnancy, because of the risk of fulminant liver
failure if it is stopped. Many successful pregnancies have occurred in women
treated with penicillamine and trientine. Infants of Wilson's disease mothers
present no particular problems. Assuming that there is no parental consanguinity,
the risk that the baby has Wilson's disease is approximately 1:200; though
all will be obligate heterozygotes (i.e. will carry the genetic fault see
diagrams VI-VII). Breast feeding is not contraindicated.
| Diagram VI
In this example dad
has Wilson's disease (2 orange
triangles). Each baby will be an obligate heterozygote. That is to
say the child will be unaffected but carry the genetic fault (one
orange triangle and one blue square).
This is just an example; it would also have been the same outcome
if mum had Wilson's disease and dad did not.
| |
Unaffected child - carries the genetic fault |
|
| Diagram VII
In this example mum has Wilson's
disease (2 orange triangles) and dad is an unaffected carrier of the
genetic fault. In this example there is a 50% probability that the
baby will inherit Wilson's disease.
| |
Unaffected child - carries the genetic fault |
| |
Child that has Wilson's disease |
|
Back to top
| Is
carrier detection available? |
If you have
Wilson's disease it is very difficult at present to reliably determine whether
your partner is a carrier (diagram VII), for which the risk is low, approximately
1:100, or not (diagram VI). However, as this distinction generally cannot
be made, it may be advisable to screen your child for Wilson's disease, although
the chance that this has actually happened is low, i.e. around 1:200 (50%
of 1:100). As the copper build up is slow, reliable biochemical screening
can only be done when your child is a few years of age. Repeating this examination
might also be necessary, sometimes more than once, as it may be difficult
to make a final distinction between carriers (i.e. non-affected) and patients.
Back to top
| Anaemia : |
A deficiency of red blood cells |
| Bile : |
A fluid that is secreted by the liver, stored in the gallbladder,
and discharged into the duodenum and aids in the emulsification, digestion,
and absorption of fats |
| Biochemical : |
The study of the chemical substances and vital processes occurring
in living organisms |
| Caeruloplasmin : |
A copper containing blood protein synthesized by the liver and
released into the blood. The normal caeruloplasmin level is 20-35 mg/100
ml of blood. Wilson's disease patients often exhibit low levels of serum
caeruloplasmin. |
| Cerebral imaging or MRI : |
This is a noninvasive technique of magnetique resonance imaging
to detect cerebral abnormalities |
| Cirrhosis : |
A chronic disease of the liver characterized by the replacement
of normal tissue with fibrous tissue and the loss of functional liver
cells |
| Consanguinity : |
Relationship by blood or by a common ancestor |
| Copper : |
Copper is a metallic element which is a necessary nutrient for
normal growth and development. An average diet provides about 2mg of
copper per day. The body only requires some of this copper and the excess
must be eliminated from the body. |
| Chelator : |
Chelators are effective anti-copper drugs. They reduce the body's
level of copper by increasing the amount of copper excreted in the urine.
Trientine
and penicillamine are chelators |
| DNA : |
A nucleic acid consisting of large molecules shaped like a double
helix; associated with the transmission of genetic information |
| Genes : |
These are sections of DNA that are carried on the chromosomes
and determine specific human characteristics, such as height or hair
colour |
| Hepatomegaly : |
Abnormal enlargement of the liver |
| Fulminant : |
Occurring suddenly, rapidly, and with great severity or intensity |
| Jaundice : |
This is a yellow colour of the whites of the eyes due to a yellow
pigment called bilirubin. Normally the liver clears bilirubin away from
the bloodstream. If the liver is not working perfectly, the yellow bilirubin
may stay in the blood. |
| Kayser-Fleischer rings : |
Copper accumulation in the eye may cause a golden-brown ring to
form around the edge of the iris. This ring is only visible using a
special instrument (slit-lamp) and is rarely present before the age
of 10 years. |
| Liver Biopsy : |
Liver biopsy is a medical procedure performed in order to obtain
a small sample of the liver. This is accomplished with a special needle,
and does not leave a scar. |
| Maintenance therapy : |
Lifelong therapy with anticopper drugs to prevent the reaccumulation
of copper and copper toxicity. This phase of therapy occurs in patients
who present with symptoms after copper toxicity has been brought under
control by initial therapy. In presymptomatic patients, maintenance
therapy begins when therapy is started. During maintenance therapy,
monitoring for the long-term compliance with anticopper medications
is necessary. |
| Metallothionein : |
A metal binding protein found in most tissues. When it binds to
copper, metallothionein renders the copper non-toxic. |
| Pre-symptomatic : |
The disease has been diagnosed, but no symptoms have manifested |
| Zinc : |
an effective
anticopper treatment. Zinc acts by stimulating the production of metallothionein
in intestinal cells. This metallothionein binds to the copper from foods
and from gastrointestinal track secretions and therefore prevents its
absorption into the body. |
If you have
any queries regarding your treatment or any other aspect of Wilson's disease
please contact your doctor.
> Living
with Wilson's > Wilson's disease
for younger people
> Living
with Wilson's > Links to patient
associations
> For medical professionals > Clinical presentation
HOW MAY WILSON DISEASE PRESENT?
Wilson disease may
come to light in an individual in a variety of different ways. Indeed, one
of the mysteries of this condition is that the same genetic abnormality can
produce such different clinical problems in different people.
- When brothers and sisters of
a patient with Wilson disease are tested, they are sometimes found to be affected.
This usually applies to younger brothers and sisters. Genetic testing
can be done immediately after birth.
- If the blood tests which primary
care practitioners take in patients with minor illnesses include liver
function tests, abnormalities can occasionally be found which on further
investigation prove to be Wilson disease
|
ACTION POINT
If "routine
liver function tests" are inexplicably abnormal in a child, test
for Wilson disease |
- Haemolysis can sometime be
the first manifestation of Wilson disease, without clinical evidence of liver disease.
It may resolve spontaneously, and liver problems may not appear until
a year or more later.
- Haemolysis may present simultaneously
with liver disease
|
ACTION POINT
In a child with
haemolysis and negative Coombs test, remember to exclude Wilson
disease |
| The liver manifestations of Wilson disease may be of almost any variety and
severity. The important practical message therefore is: suspect Wilson
disease in any child with undiagnosed liver disease. Presentations include:
- finding abnormal liver function
tests as above, even as early as the first year of life
- finding enlargement of the liver on clinical examination,
either in a routine check of an asymptomatic child or during examination
of a neurologically affected case.
- an acute hepatitis which appears to resolve. Failure
to find a viral aetiology for an acute hepatitis, or delayed or incomplete
resolution, should raise the possibility of Wilson
disease
- "chronic hepatitis"
i.e. continuing abnormality of liver function tests, clinically indistinguishable
from an autoimmune hepatitis, though usually not having raised plasma
globulin or autoantibodies in the serum
- variceal haemorrhage from unsuspected
portal hypertension,
- signs of decompensated chronic
liver failure
- fulminant liver failure (FHF). This, the most urgent presentation,
causes the most difficulty in diagnosis and management. It usually
occurs without antecedent illness but may occasionally be precipitated
by an infection. Previous episodes of haemolysis
or 'hepatitis' may have occurred.
|
CLUES suggesting Wilson
disease in a child with fulminant liver failure are
- absence of other known causes;
- a relevant family history;
- disproportionate rise in bilirubin
(>300micromol/l);
- haemolysis on blood film;
- relatively low alkaline phosphatase (<600iu/l) or transaminases
(100-500iu/l).
|
| The neurological
manifestations of Wilson disease are diverse and may present as movement disorders
which can be quite difficult to differentiate from other neurological
disorders. They include:
- A dystonic syndrome characterized
by dystonic postures and choreoathetosis
- An ataxic syndrome with postural
and intentional tremor and ataxia of the limbs
- A parkinsonian syndrome with
hypokinesia, rigidity and resting tremor
These three
syndromes often occur in the same patient or develop as the disease
progresses. Experience in 188 patients (Czlonkowska unpublished data)
suggests that the most frequent syndromes are:
- Dysdiadochokinesia (present
in all investigated patients)
- Postural tremor (wing-beating
in 56%)
- Dysarthria (93%)
- Salivation (93%)
- Gait disturbances (79%)
|
CLUES suggesting Wilson disease are:
- Wing-beating
- Postural tremor of the arms
- Dystonic posture of the stretched
arm behind the back
- Fixed pseudo-smile (risus sardonicus)
- Dysarthria
|
| Psychiatric
disorders are quite variable. Depression is common. Neurotic behavior
includes phobias, compulsive behaviors, aggression, or anti-social behavior.
Cognitive deterioration may also occur with worsening school performance,
poor memory, difficulty in abstract thinking, and shortened attention
span. Pure psychotic disorders are uncommon. |
ACTION POINT
Parents' concerns
about changes in mood or school performance in a teenager, especially
with speech slurring, must be taken seriously. Wilson disease is a rare but possible cause. |
Usually, the
ophthalmologist is asked to look for eye abnormalities in a patient already
suspected of having Wilson disease.
Occasionally the optometrist or ophthalmologist may be the first to suspect
Wilson disease because of finding
the characteristic eye abnormalities
The Kayser-Fleischer
ring is a gold or gray-brown opacity in the peripheral cornea. It first develops
superiorly in the cornea (12 o'clock), then inferiorly, and finally in the
horizontal meridian. It represents a deposit of copper and sulfur-rich granules
in Descemet's membrane, and is reversible with treatment. Additional later
ocular findings in Wilson disease include sunflower cataracts, saccadic pursuit movements,
loss of accommodation response, and apraxia of opening the eyelid.
| RENAL
OR SKELETAL ABNORMALITIES |
They are very
occasionally the first signs of Wilson disease.
> For medical professionals > Diagnosis
The diagnosis of WD is
based on a combination of clinical, biochemical and genetic tests.
Summary of tests performed for the diagnosis of Wilson disease
24 h urinary copper
Serum copper
Plasma caeruloplasmin
Liver copper and histology
Neuroimaging
Molecular biology
Clinical tests
Scoring system
Fulminant hepatic failure
| Tests performed for the diagnosis of Wilson disease |
| TEST |
COMMENTS |
| Urinary Copper |
24 hour copper excretion >100µg in 65% of WD patients |
| Urinary copper penicillamine challenge with two dosages of 500mg
12 hours apart and measure urine copper |
24 hour copper excretion > 1600 µg in patients with active
liver disease |
| Serum Copper |
Serum copper may be low in asymptomatic cases (because caeruloplasmin
is low) or high in cases with active liver disease (because free copper
is raised) |
| Serum "free" copper
Calculated on the basis that caeruloplasmin contains 0.3% copper |
Free Copper >25µg/dl |
| Serum Caeruloplasmin |
< 20 mg/dl (in 95% of WD patients) |
| KF rings |
Identification in most patients requires an experienced observer |
| Liver Copper |
>250 µg/gm of dry weight liver |
| Coombs negative haemolytic anaemia |
|
| Biochemical indices |
Abnormal liver function tests |
| MRI scan |
Abnormal |
| Molecular diagnosis |
Over 200 mutations are known |
Back
to top
The 24h urinary
copper value may be misleading because of incorrect 24h urine collection,
especially in pediatric patients, for whom 24h urine collection is not very
easy. The penicillamine challenge test was evaluated in patients presenting
with liver disease, in whom it has high sensitivity,
but its sensitivity in asymptomatic patients is low and it has not been evaluated
in adult neurologically presenting cases. Back
to top
The total serum
copper varies in different clinical scenarios in Wilson disease, because it may be low as a result
of low caeruloplasmin, or elevated as a result of release of free copper from
a damaged liver. Free serum copper, calculated as [total copper - 0.3% caeruloplasmin]
suffers from the fact that is is based on two laboratory measurements and
thus has wide confidence intervals. It is no longer considered to be a reliable
diagnostic tool. Back
to top
Although, low
plasma caeruloplasmin is reported in 73% of WD patients1, false negatives
have been observed in cases of infection, pregnancy and estrogens intake,
because it is an acute phase reactant. On the other hand, false positive data
may be observed in heterozygotes (20%), protein-losing enteropathy, aceruloplasminemia
and severe hepatic insufficiency. The method used by the laboratory (the oxidative
assay or nephlometric assay) may also affect the results of caeruloplasmin
measurement2. Back
to top
Liver copper
values equal to or higher than 250 µg/gm of dry weight are considered to be
the gold standard in the diagnosis of Wilson's disease. In chronic cholestatic
conditions the liver copper content is also elevated, but in childhood this
usually does not cause diagnostic confusion. Ferenci et al. (in press) assessed
the hepatic copper content of 106 patients at the time of diagnosis of Wilson
disease. The distribution of hepatic copper concentration as a function of
histological findings showed that 19 Wilson
disease patients had a liver copper concentration below 250 µg/g dry weight.
The sensitivity analysis based on comparison of these 106 patients to 244
other patients without Wilson disease
showed that the upper limit of diagnosis (>250µg/g dry weight) has a poor
sensitivity (82%) and very good specificity. The low range (50µg/g dry weight)
has a higher sensitivity, but lower specificity as well as a positive predictive
value. The negative predictive value shows a major gain. Further studies are
required to confirm these data. There are fewer data on liver copper in patients
with a neurological presentation.Back
to top
Hepatic manifestations
of Wilson disease are very similar
to those observed in autoimmune hepatitis, steatosis, and fulminant hepatic
failure. Copper and copper-associated protein may be seen histochemically,
but their absence does not exclude a diagnosis of Wilson disease, particularly in childhood.Back
to top
Neuroimaging
techniques, such as computed tomography (CT) and magnetic resonance imaging
(MRI) of the brain, play an important role in the diagnosis of Wilson
disease presenting neurologically. In CT, ventricular dilatation, cortical
atrophy and brainstem atrophy is seen more frequently than bilateral hypodense
areas in the basal ganglia. Experience from 109 cases shows that cortical
atrophy was found in 83 (76%) of patients with a neurological presentation
(basal ganglia hypodensity in 28 of 109)(Czlonkowska
unpublished data)MRI is the most important diagnostic tool in patients with
neurological presentation. Almost all patients show an MRI abnormality. MRI
detects non-specific changes in the brain such as diffuse brain atrophy and
focal abnormalities. These are shown as increased signal activity on T2-weight
images in lenticular, thalamic and caudate nuclei as well as in the brain
stem, cerebellum and white matter. It has been shown that the most frequent
abnormalities are (Czlonkowska, unpublished data):
- Putamen (61%)
- Globus pallidus (59%)
- Brainstem and cerebellum (34%)
Magnetic resonance
spectroscopy (MRS) can also detect heavy copper accumulation in brain matter
and be a noninvasive study of brain metabolism. By this technique N-acetylasparatate
(NAA), choline containing compounds (Cho), creatine and phosphocreatine (Cr),
lactate and other amino acids can be observed noninvasively. In adult patients
with Wilson disease the MRS study shows decreased NAA/Cr and Cho/Cr ratios
in the left and right globi pallidus.Back
to top
In recent years
the developments of new techniques in genetic and molecular biology have provided
useful tools in the diagnosis of Wilson disease. Ferenci et al. have studied DNA
from 754 patients. Using polymerase chain reaction (PCR), mutation analysis
was first performed to detect the H1069Q mutation, which is the most common
mutation among the WD patients of central, eastern and northern European origin.
Further mutation analysis was performed in the absence of the H1069Q mutation.
Amongst 635 index cases studied so far, 87% of patients had at least one known
mutation (in 54% both mutations were identified, 33% had only one known mutation).
In 13% of cases no mutation was identified. This is to some extent due to
the fact that this is an ongoing study, where exons 2 to 7, 9, and 21 were
not yet analysed.The distributions of WD mutations according to clinical presentation
of the disease as well as the age at onset of either neurological or hepatic
symptoms were also assessed: Click to enlarge the table.In this series the H1069Q homozygote mutation,
associated with late onset neurologic disease, was mainly detected in neurological
presentations. This was also the case of the H1069Q/ 3400delC mutation. Hepatic
presentation of WD mutations was mainly associated with mutations affecting
exon 8. Back to top
| Clinical tests : the Kayser Fleischer ring |
The diagnostic
value of the KF ring is not the same for patients with neurological and hepatic
disease. In a study conducted by Steindl et al only 50% of hepatic patients
were found to have KF rings, while KF rings were detected in 90% of neurological
patients. Back
to top
In 2001 at
the 8th international conference on WD and Menkes disease a scoring system
for the diagnosis of WD was discussed3. The aim was
to provide objective criteria with high sensitivity and specificity for the
diagnosis of Wilson disease. A combination
of clinical and biochemical tests with a score ranging from 0 to 4 for each
test were developed.
Click to enlarge the table.
The patients
with a total score of at least 4 were diagnosed with Wilson's disease. The
patients with a total score of two to three were considered as "likely
to have Wilson's disease, yet more investigations had to be performed".
The diagnosis of Wilson's disease was judged to be improbable for scores between
zero and one. With respect to molecular analysis, it should be noted that
more than 200 different mutations have been identified. It has been difficult
to devise a simple genetic screening test for the disease. Thus only the H1069Q
(exon 14), was researched.
In order to test this scoring system, 143 children with chronic liver disease,
aged at least 5 years, were reviewed. All patients had urinary copper assessments
and a liver biopsy as part of the diagnostic work up.
Evaluation of the Leipzig meeting score: Click to enlarge the table.Fifty patients with Wilson disease had a score >= 4 (true positives).
A total of 85 true negatives with a score of either 2-3 (40 children) or <
1 (45 children) were observed. Only 3 patients with Wilson
disease had a score of 2 to 3 (false negatives), while 5 non Wilson
disease patients had a score of at least 4 (false positives). Both sensitivity
and specificity of this scoring system was higher than 94%. In addition, positive
predictive value and negative predictive values were higher than 90% (90.9%
and 96.59% respectively).Back
to top
| Fulminant hepatic failure |
As previously
mentioned, hepatic failure is a common feature of WD, predominantly reported
in females (75% versus 25% in males). The patients with fulminant presentation
of WD, defined as acute liver disease with encephalopathy, have a high mortality
(almost 100%) in the absence of transplantation. In order to assess survival
in FHF patients a prognostic index based on the SBR, AST and INR values has
been developed4. The results
showed that among the 27 patients included in this study all patients with
a score of at least 7 died. The sensitivity and specificity of the test were
respectively 87% and 90%, with a likelihood ratio of 8.7. This scoring system
has been re-evaluated by Dhawan et al. The medical records of children with
Wilson disease, in particular
those with fulminant Wilson disease, admitted to King's
College Hospital (London, UK)
were reviewed retrospectively. Between 1967 and 2000, 74 children (46 boys
and 28 girls) with a median age of 11.7 years (2.6-17.9 years) were admitted
to the hospital. All children with at least two positive tests out of the
following list were diagnosed with Wilson
disease.
- Family history
- KF rings
- Low Caeruloplasmin
- Coombs' negative haemolytic anaemia
- Elevated 24-Urinary copper
- Elevated liver copper
- Positive penicillamine challenge
Elevated urinary copper, low caeruloplasmin, KF rings and anemia
were reported in half of patients. Elevated liver copper and family history
were noted in respectively 76% and 17% of patients.
Diagnosis of Wilson
diseaseClick to enlarge the table.
More than half
of the children (54.7%) had jaundice. Acute liver failure and abdominal pain
were reported in respectively 36% and 32% of patients. Lethargy and encephalopathy
were observed in almost one third of patients.
Clinical presentations of Wilson's disease 74 children admitted to King's
college Hospital
Click to enlarge the table.Among these patients,
17 fulminant presentations of WD were observed. Nine were male and 8 female,
with a median age of 11.9 (8.6-16) years. In WD patients with fulminant presentation,
diagnosis is even more challenging, due to the lethal condition of the disease,
which requires a rapid diagnosis associated with difficulties performing biochemical
tests, especially the 24H urinary copper (caused by renal insufficiency).The
data obtained in all patients were analysed retrospectively, using bilirubin,
white cell counts, INR, albumin and AST values at presentation as predictors
of mortality. Authors proposed a new predictive index value of 11 with a higher
likelihood ratio than the previous scoring system (22.8 vs 8.7), as well as
higher sensitivity and specificity (93% and 96% compared to 87% and 90% respectively).
Back to top
1Steindl P.,
Ferenci P., Dienes HP., Grimm G., Pabinger I., Madl Ch., Maier-Dobersberger
Th., Herneth A., Dragosics B., Meryn S., Knoflach P., Granditsch G., Gangl
A. Wilson´s disease in patients presenting with liver disease: a diagnostic
challenge. Gastroenterology, 1997, 113 : 212-18.
2Cauza E., Maier-Dobersberger
Th., Kaserer K., Kramer L., Ferenci P.Screening for Wilson´s disease in patients
with liver diseases by serum ceruloplasmin. J. Hepatol., 1997, 27 : 358-362
38th International
conference on Wilson's disease and Menkes Disease. Leipzig/ Germany,
April 16-18, 2001
4Nazer H., Ede
RJ., Mowat., Williams R. Wilson's disease: clinical
presentation and use of prognostic index. Gut. 1986,
27 : 1377-1381
> For medical professionals > Treatment
The treatment
of Wilson disease was impractical until J.M. Walshe, in
1956, described the favourable effects of this copper-chelating therapy in
Wilson disease. In almost all asymptomatic
patients and many symptomatic patients penicillamine therapy can prevent or
repair the devastating effects of the copper overload. However, side effects
and toxic reactions are frequently observed and in 10% of the patients therapy
has to be stopped. Also, a significant proportion of the patients with neurological
disease experience worsening of their neurological symptoms after starting
penicillamine, and some of them will never return to their pre-penicillamine
base-line again. Therapeutic alternatives have therefore been sought. The
first to appear was trientine, another copper-chelating agent which seems
to have the same results as penicillamine. A new and promising alternative
is tetrathiomolybdate, which is evaluated at present in several clinical trials.
In 1961 Schouwink
introduced zinc as an alternative to penicillamine. He described that during
zinc treatment the amount of copper excreted with the stools increased, making
overall copper balance negative. This effect is now known to be based on zinc-induced
metallothionein synthesis in the small intestinal epithelium. The metallothionein
binds copper and the complex is sloughed of into the faeces together with
the intestinal cell. Especially during the last 10 years zinc has gained increasing
acceptance as it has been shown sufficiently that oral zinc is a suitable
alternative to penicillamine as long-term maintenance therapy both for adults
and children with Wilson disease. Zinc also seems to be safe in presymptomatic
patients.
A special treatment
problem is the patient with severe liver disease and impending liver failure.
In these patients penicillamine will fail in up to 50%. Nevertheless this
medication should be started as soon as the diagnosis has been made. However
when, despite therapy, liver synthesis function deteriorates further, liver
transplantation should be performed. Liver transplantation is also done in
patients with end-stage liver disease due to advanced cirrhosis.
Present therapy
will improve symptoms and prevent a fatal outcome in most patients. However,
for patients with neurological disease the symptoms may not all be reversible.
For patients presenting with mild liver problems, residual morbidity seems
to be confined to the presence of cirrhosis in some, while in pre-symptomatic
patients therapy prevents the onset of symptoms altogether. For all patients
compliance with the life-long continuous treatment is of paramount importance.
Stopping medication will lead to severe organ damage, or even death, within
a time-period that can be as short as a couple of months.
> For medical professionals > Pregnancy in WD
Wilson disease itself is not
a reason for avoiding pregnancy. It is very important that treatment is continued
throughout the pregnancy, because of the risk of deterioration of liver or
neurological disease if it is stopped. Your physician will guide you about
choice of medicines and doses, and about monitoring your treatment throughout
pregnancy. However, before embarking on a pregnancy, women with Wilson
disease need to have a detailed discussion with their physician about all
aspects of their health. For
example, severe liver disease may pose significant problems.
> For medical professionals > Links
| |
| http://abpmaladiewilson.free.fr |
Association Francophone pour l'étude de la maladie de Wilson |
| BSPGHAN |
British Society of Pediatric Gastroenterology Hepatology
and Nutrition |
| NINDS |
National Institute of Neurological Disorders and
Stroke Wilson's Disease Information page |
| OMIM
|
(Online Mendelian Inheritance in Man)
Search for Wilson disease |
| PEDIHEPA |
Website dedicated to pediatric hepatology - liver diseases
in children |
| PUBMED |
Publication database |
| SNFGE |
Société nationale française de gastroentérologie |
| Wemove |
World wide education and awareness for movement disorders |
| http://www.uofa-medical-genetics.org/wilson/index.php |
Wilson disease mutation database |
|
> For medical professionals > Laboratory services
A small number
of specialist laboratories have developed molecular diagnostic tests for Wilson
disease. As a part of the EuroWilson project, these laboratories are forming
a network in which there will be collaboration and a quality assurance scheme.
Techniques have rapidly improved, and there are now rapid methods for detecting
the common mutations. Rapid sequencing has also made it much easier to detect
less common or previously unknown mutations.
Consideration
will also be given to the availability of facilities for liver copper assay
and its quality assurance.
> Disclaimer
The EuroWilson website contains information about Wilson disease that we believe might be of interest
to patients, family members and health care professionals. We strive to ensure
that the contents are correct and up-to-date. The website is under the responsibility
of a scientific committee whose members all have expertise in Wilson
disease. Its object is to disseminate information, but not to be a substitute
for consultation with healthcare professionals. It must be emphasized that
each patient is unique, and that only a patient's physician can provide appropriate
and individual information and care. The EuroWilson consortium cannot be held
responsible for harmful, truncated or erroneous use of any information found
on this website.
> About EuroWilson > Project summary
Select individual
topics by clicking on title. Alternatively the information may be printed
as a PDF file
ParticipateWilson disease (WD)
is an autosomal recessive disorder in which deficiency of a copper-transporting
trans-golgi P-type ATPase leads to intracellular retention of copper. Prevalence
estimates vary from 1/30,000 to 1/100,000. Wilson disease (WD) patients are
disseminated all over the world presenting with a wide range of heterogeneous
clinical syndromes including hepatic, neurological or psychiatric presentations.The
main clinical and biochemical features of Wilson's disease are well known,
and the history of Wilson disease represents a triumph of progressive discovery
and application of science, but still a large number of questions remain unanswered:
- What is the incidence and prevalence
of different subgroups?
- How to treat pre-symptomatically
diagnosed infants?
- Are there genetic or environmental
modifiers?
- How to define diagnosis including
genetic testing?
- Short and long term outcome of
current treatments?
> About EuroWilson > Objectives
- Set up a clinical database
- Plan a randomized controlled
trial, or trials, in Wilson disease
> About EuroWilson > Participate in EuroWilson
The primary aim of the EuroWilson database is to collect data on all newly presenting
cases of Wilson disease. If you would like to participate or have questions
about the registry, please complete the following questionnaire
> About EuroWilson > About EU framework six funding
The Sixth Framework
Programme (FP6) is the European Union's main instrument for the funding of
research and innovation in science, engineering & technology. It is open
to EU public and private entities of all sizes, and incorporates provision
for the participation of non-EU countries. Funding is structured around three
key targets aiming to implement the European Research Area. For
more information consult the
Sixth Framework Programme website.
> Latest information > Latest News
| Wilson
disease: the challenges |
|
|
| |
| GeNeMove and EuroWilson jointly organised a workshop during
the Falk www.drfalkpharma.de symposium at Freiburg. |
|
|
| |
| |
| Members from EuroWilson, GeNeMove and the French Speaking
Association of Wilson disease well meet in Warsaw
on November 27 to discuss and test the neurolgocal aspects of
the database |
|
|
| |
| |
| The EuroWilson Consortium
met in Prague. The main objectives were to agree upon the items to be
collected on the WD database and to discuss methods of identifying
data entering clinicians in EU countries. 1.The
database questionnaire is now complete; HC Forum will produce
the web-based platform, which will be tested on patients before
its launch in January 2005. Notably a meeting of eminent neurologists
and hepatologists will be held in Warsaw
on November 27th to experience the database on 10 neurological
presenting patients. 2.Piotr Socha
and Jacques Sarles are leading the dissemination working groups;
their aim is to identify the clinicians managing large numbers
of Wilson disease patients
in the EU. It would be logical that these individuals become
data entering clinicians. Training of data entering clinicians
will begin in January 2005. It was agreed to establish a formal
collaboration with l’association francophone pour l’étude de
la maladie de Wilson, GeNeMove (Deutsches Netzwerk für erbliche
bewegungsstörungen) and the British Neurological Surveillance
Unit. The first two groups will also be collecting data on existing
patients. The following points were also discussed: 3.Hartmut
Schmidt was nominated as deputy co-ordinator of the EuroWilson
project. Professor Schmidt is also leading the submission for
Marie-Curie funding for research into Wilson
disease. 4.The next EuroWilson consortium meeting will be held
on 15 & 16 of January 2005 |
|
|
| Laboratory
Network Meeting |
|
|
| |
| The first EuroWilson
laboratory meeting was held in Prague at
the Charles II University Hospital
and included groups from Austria, Berlin, Lyon,
Prague, Sardinia, Sheffield, Utrecht and Warsaw. They
discussed techniques and results and agreed to set up a quality
assurance scheme and a polymorphism forum on the web.
|
|
|
| EuroWilson
Database Meeting |
|
|
| |
| Participants: Oliver Bandmann (UK) Anna Czlonkowska (EuroWilson
Consortium Member) Christophe Durand (HC Forum IT Manager) Michel
Haguenau (France) Carsten Möller (GeNeMove Wilson Disease Coordinator)
Samantha
Parker (EuroWilson Programme Manager) Hartmut Schmidt (EuroWilson
Consortium Member) Stuart Tanner (EuroWilson Coordinator) France
Woimant (French Society President) Aim of the meeting: Agree
on a common Wilson disease database particularly with regard
to the neurological components Summary: The meeting considered
the neurological component of the database to be used by EuroWilson,
the French Association for the Study of Wilson Disease and GeNeMove.
Drafts prepared by Prof Anna Czlonowska and Dr Carsten Möller's
group were discussed in detail. The group carefully considered
the need to allow for complete recording of physical signs whilst
not making data entry excessively complex. Agreement was reached
on all points of detail, and a draft will be circulated. |
|
> Latest information > Newsletter
| |
Main purpose
- Find how many patients are being diagnosed with
WD
- What kinds of clinical problems they have
- Whether it will be possible to set up good clinical
trials
Benefits
- A resource for patients and professionals
- Learn about current treatments and their short-term
outcome
- Set up a laboratory quality assurance scheme
- Raise awareness
- Improve long term welfare of affected
people
|
|
Dec
04 / Jan 05
EuroWilson is an EU
funded project to set up a database of all newly presenting cases
of Wilson disease (WD) throughout Europe. It aims to find out how many new cases there are, what sorts
of clinical problems they have, and whether it will be possible
to set up high quality clinical trials of different treatments.
Every doctor treating a newly diagnosed case of WD is invited
to join Eurowilson. For more information on participating contact us.
So, why EuroWilson, and why a newsletter?
We have several treatments
for Wilson disease (WD)
– penicillamine, trientine, zinc – but
- Which is the best one for a particular patient?
- Which is most likely to bring the liver disease under
control and prevent the development of cirrhosis?
- Which will be best at preventing neurological deterioration?
- Which has the least side-effects, and which gives
the best long-term results?
- How should we treat the asymptomatic sibling?
- How should we treat pregnant and nursing women?
These are questions
about which there are many opinions, but virtually no data derived
from randomised controlled clinical trials of sufficient size
and quality to give a definite answer. Before we can even think
about setting up a trial, we have to know how many patients there
will be – in statistical terms, will the trial be adequately powered?
And in WD, of course, we have the additional complication that
we have several different types of patient – the child with liver
disease (of several different kinds), the older patient with neurological
problems, and some patients with less common problems like haemolysis.
- To report briefly on what is going on
- To
enlist your help
Eurowilson will only
succeed if everybody concerned with WD in Europe
supports it. It is important that every newly presenting patient
is entered on the database in all participating countries.
| |
A website has
been created, with sections for professionals and sections
for the public. It contains more information about EuroWilson,
and as a matter of principle carries a short note of all
consortium meetings
www.eurowilson.org |
Completing the database Neurologists, pediatric and adult hepatologists, laboratory scientists
and experienced database engineers are finalizing a sophisticated,
easy to use, secure Wilson disease database. It is planned to begin data entry in January
2005. Establishing contacts for database
entry Every doctor treating a newly
diagnosed case of Wilson
disease is invited to join EuroWilson. For more information on
participating contact us. Research ethical approval Research
ethical approval is being obtained in each participating country.
The UK MREC number is 04/MRE04/65. Examples of the consent forms
and information sheets for young people, parents, and adult patients
can be found on the EuroWilson web page. More Genetics laboratories A
group of molecular biologists from laboratories offering WD diagnosis
met at the Children’s Hospital in Prague on 26 September 2004. They discussed
techniques and results and agreed to set up a quality assurance
scheme. Contact
laboratory group manager Partner organisationsL'association Francophone pour l'étude de la maladie de WilsonThe French Association for the study of Wilson disease
is a newly formed network of hepatologists, neurologists, paediatricians
and scientists who will be using the EuroWilson database to record
their existing patients - and, of course, the newly presenting
ones who will be included in the EuroWilson analysis. Contact GeNeMove
| |
GeNeMove is a collaboration
of neurologists establishing databases of patients with
Wilson disease and other disorders. GeNeMove
has made a big contribution to work on the neurological
part of the database. GeNeMove will also be collecting data
on existing patients. GeNeMove and EuroWilson jointly organised
a workshop during the Falk symposium at Freiburg
on October 15, 2004. More
; contact |
| The British Neurological
Surveillance Unit mails all UK
neurologists monthly to collect data on rare neurological
diseases, and will include Wilson
disease during the study. More. |
|
For more information on participating
contact us |
|
Vivre avec la maladie de Wilson > Guide de la maladie de Wilson
Le contenu est
détaillé ci-dessus, sélectionner les différents sujets abordés en cliquant
sur leur titre.
| Qu'est-ce
que la maladie de Wilson ? |
C'est une malade héréditaire
dans laquelle le cuivre de l'organisme n'est pas éliminé correctement. L'excès
de cuivre s'accumule dans le foie ou le cerveau causant des problèmes hépatiques
ou neurologiques. Le cuivre peut aussi s'accumuler dans d'autres organes comme
les yeux ou les reins.
L'accumulation commence dès la naissance mais les premiers symptômes n'apparaissent
en général qu'après l'âge de 10 ou 20 ans. Les premiers signes sont hépatiques
dans 40% des cas, neurologiques dans 35% et psychiatriques, rénaux, hématologiques
(sanguin), ou endocrinologiques (glandes) dans les autres cas. Haut
de la page
| Quels
sont les symptômes? |
Dans certains cas, les
symptômes sont banals mais présents au quotidien : fatigue, perte d'appétit,
douleurs abdominales, vomissements, perte de poids, saignements de nez et
anémie, douleurs articulaires. Ces symptômes peuvent être chroniques et persistants
ou évoluer par poussées plus ou moins durables. Dans d'autres cas, les symptômes
peuvent être plus aigus, particulièrement quand le foie est atteint.
Les maladies de foie sont généralement divisées en :
- Maladie de foie aiguë. Souvent
responsable d'un ictère (jaunisse). Une transplantation du foie en urgence
peut être nécessaire si le traitement n'entraîne pas une amélioration rapide.
- Maladie chronique du foie : Les
lésions du foie aboutissent lentement à une dégradation sévère du foie.
Là aussi, une greffe du foie peut être nécessaire.
Les problèmes neurologiques
observés sont :
- détérioration des performances
scolaires et d'écriture
- tremblementss
- dystonie: crampes des bras et
des jambes qui , en l'absence de traitement, peuvent
aboutir à des contractures généralisées.
- ataxie: perte de coordination
- rigidité musculaire
- dysarthrie: problèmes de langages.
Dans le cas de la maladie de Wilson les signes de la dysarthie varient d'une
personne à l'autre : des insultes, faible volume de la voix, répétition
de certain mots. Dans les cas extrêmes les patients
sont dans l'incapacité de parler (anarthrie).
Environ un tiers des patients présente des troubles psychiatriques incluant
état dépressif, changements de la personnalité et de l'humeur. Haut
de la page
Le cuivre est présent dans
la majorité des aliments et est nécessaire pour la croissance et le développement.
Les schémas I-IV illustrent le métabolisme du cuivre chez les sujets sains,
et des sujets atteints de la maladie de Wilson (avec et sans traitement).
| Schéma I : sujet sain
: absorption et élimination sont bien équilibrées |
| Schéma II : sujet atteint
de la maladie de Wilson : élimination réduite et accumulation du cuivre |
| Schéma III : sujet atteint
de la maladie de Wilson traité par le zinc : accroissement d'élimination
fécale du cuivre |
| Schéma IV : sujet atteint
de la maladie de Wilson traité par un chélateur |
Haut
de la page
| Comment
la maladie de Wilson est-elle transmise? |
La maladie de Wilson est
une maladie génétique qui atteint indifféremment les filles et les garçons
(maladie autosomique). Elle est due à une anomalie d'un gène qui intervient
dans le métabolisme du cuivre. Les sujets atteints de cette maladie ont reçu
de leur père et de leur mère une forme anormale de ce gène (maladie récessive).
Cette anomalie est appelée " mutation ". C'est parce que leurs 2
gènes sont anormaux (mutés) qu'ils sont malades. Les parents, qui sont en
bonne santé, sont dits " porteurs sains " (ou hétérozygotes). Ils
ont un gène anormal et un gène normal qui suffit à permettre un métabolisme
normal du cuivre. La fréquence de cette maladie est très faible : 1 sur 30 000 a 50 000 naissances. Haut
de la page
| Comment
cela arrive-t-il? |
Le schéma V montre comment
cela se produit.
| Schéma V
| |
Enfant non atteint - n’est pas porteur du gène défectueux |
| |
Enfant non atteint - porte un gène défectueux |
| |
Enfant ayant la maladie de Wilson - porte deux gènes défectueux
|
| |
Enfant non atteint - porte un gène défectueux |
Le père et la mère portent une anomalie du gène de la maladie de
Wilson (triangle orange). Ils sont en bonne santé. Dans ce cas, à
chaque grossesse il y a 25% (1 sur 4) de risque d'avoir un enfant
atteint de la maladie de Wilson |
Haut
de la page
| Diagnostic
de la maladie de Wilson |
Le diagnostic peut être
fait à partir de tests relativement simples. Ces tests peuvent diagnostiquer
la maladie chez des personnes déjà malades ou avant l'apparition des symptômes
(diagnostic pré-symptômatique). L'accumulation de cuivre dans l'oeil crée
au bout d'un certain nombre d'années un anneau de cuivre autour de
This project is supported through Priority 1 (Life Sciences, Genomics and Biotechnology for Health) of European Union's FP6