Wilson's disease (WD) occurs
all over the world and has an incidence of 1 in 30,000. The disease can
manifest at any age but it mostly appears between 5-35 yrs.
In most humans, the
intake of copper through diet far exceeds the metabolic need and a balance is
maintained through biliary excretion.
When this function is impaired
due to a genetic abnormality, there is an accumulation of copper in the body,
including the vital organs such as the liver and the brain. The disease is
fatal if left untreated.
The first European
Clinical Practice Guidelines (CPGs) for the effective diagnosis and management
of Wilson's disease were published recently by the European Association for the
Study of the Liver (EASL). Lead author Professor Peter Ferenci said: "The
clinical presentation of Wilson's disease can vary widely, but it must be
considered in any patient who presents with a combination of unexplained liver
disease and neurological or neuropsychiatric disorders. In the absence of
Kayser-Fleischer rings which are typical but not always present, the guidelines
recommend measurement of urinary copper excretion and hepatic parenchymal
copper as diagnostic methods of choice. Notably, age alone should not be the
basis for eliminating a diagnosis of Wilson's disease."
Houwen added: "Unfortunately, as there are no optimally designed randomized
controlled trials conducted in Wilson's disease, there is a lack of
high-quality evidence to estimate the relative treatment effects of the
available drugs. Our evaluation is mostly based on large case series that have
been reported in recent decades, which highlights a clear need to conduct more
robust randomized controlled trials to better understand treatment for this
Symptoms & Signs
a) Physical signs
of Wilson's disease include the Kayser-Fleischer rings, which are present in
the majority but not all of WD patients. These rings are caused by the
deposition of copper in the cornea of the eye and can be detected by slit-lamp
examination by an expert. These rings are not exclusive to WD but can also be
found in other conditions as well.
b) Liver disease -
Liver disease in WD patients can range from being asymptomatic to overt
cirrhosis with all its complications. Any person with liver disease of unknown
origin must be evaluated for Wilson's disease until proven otherwise.
- Those with Wilson's disease may present with
neurologic, psychologic or behavioral disorders. These may be presenting symptoms
or may manifest years later. The neurologic symptoms include coarse tremors,
abnormal muscle tone and difficulty with balancing. - Facial grimacing, open
mouth, drooling, lip retraction and speech changes are some of the common
manifestations. The patient may have more than one of these symptoms with
varying degrees of severity. Eventually the WD patients with neurologic
symptoms become bed-ridden due to severe disability, although they manage to
remain alert. Behavioral and psychological symptoms are very common and tend to
precede the neurologic symptoms.
- Hemolysis or destruction of red blood cells occurs commonly
in those with severe form of liver disease. Degeneration of liver cells leads
to stored copper being released, which in turn causes more hemolysis. A test
called Coomb's test is usually negative. Low-grade hemolysis may be a
presenting symptom for those with WD without the liver disease.
A combination of Kayser-Fleischer rings along with low
levels of serum ceruloplasmin are sufficient to diagnose Wilson's disease.
are carried out to confirm the diagnosis are:
Ceruloplasmin is a most important copper carrying compound
present in the blood. It is typically low in patients with neurologic Wilson's
disease, but it can be on the lower normal range in those WD patients with
24 hr urinary copper
Determining the amount of copper excreted through urine is
extremely important in diagnosing Wilson's disease. In a symptomatic patient
who is untreated, the baseline copper excretion that is greater than 1.6
micromol/24hrs is considered as a sign of Wilson's disease. However, this value
is less in affected children and in their asymptomatic siblings. In children,
urinary copper excretion greater than 0.64 micromol/24 hours can be considered
suggestive of Wilson's disease.
- Estimation of copper accumulation in the liver tissue is the method of choice
for diagnosis of Wilson's disease. In patients with active disease or
regenerative liver nodules, the copper in the liver may display normal values,
while in those with cholestatic syndromes, the values may be high showing
(seen during slit-lamp examinations) are not
seen in 50% of those with WD and in asymptomatic siblings. However, these
rings, which are typical of WD, are also seen in those with primary biliary
WD patients also show neurologic symptoms like
those of Parkinson's disease such as rigidity, dystonia or tremor. The patients
should be thoroughly evaluated by a neurologist to confirm or rule out Wilson's
of the brain -
Imaging studies such as the MRI can
detect lesions and other abnormalities in the brain that are features of
Wilson's disease. These include the typical feature of Wilson's disease
described as the "face of the giant panda".
There are several mutations involved in bringing about Wilson's disease
therefore, genetic tests are not feasible. However, a study for the mutation in
the gene ATP7B can be carried out once a provisional diagnosis of WD has been
Liver function tests
These tests detect
acute liver damage due to Wilson's disease. It is important to
detect liver damage due to Wilson's disease, as the related death rate is
phenomenally high. Simple and accurate methods include laboratory tests to
evaluate the levels of alkaline phosphatase levels, bilirubin and serum amino
transferases. These tests must not be considered alone but must be considered
along with other signs and symptoms of Wilson's disease.
- When a patient has been identified with Wilson's disease it is important to
screen the family members as the likelihood of a sibling being homozygous for
the disease is 25%. The chance of an offspring having the disease is 0.5%.
Although the risks are low, genetic tests for close family of an affected
person is justified considering the devastating course of the disease.
Once Wilson's disease
is diagnosed, the treatment is life long. A number of drugs are available to
treat Wilson's disease.
- This drug is used in those with WD to enhance the excretion of urinary
copper. It is best taken one hour before meals, as food tends to interfere with
the drug's absorption. D-penicillamine interferes with pyridoxine action and
therefore pyridoxine supplements must be administered.
Adequecy of treatment
is monitored from the start of treatment by checking the 24-hr urinary copper
patients with liver disease, the improvement in symptoms occurs typically in
the first 2-6 months. In those patients with neurologic symptoms the
improvement is much slower. Worsening of symptoms in the latter group has also
Side- effects of the
drug include fever, skin eruptions, swelling of lymph nodes, or reduced blood
counts. These can be seen in 30% of patients administered with the drug. Other
side effects include kidney damage and a lupus-like syndrome. When the side
effects appear, drug administration has to be stopped.
Trientine, a chelator, was introduced as an alternative to D-penicillamine and
like the earlier drug, promotes urinary copper excretion. Trientine can be
administered one hour before meal or three hours after meals. It may be used in
patients developing side effects to D-penicillamine. The drug is effective in
treating WD although side-effects, including neurologic worsening and
reversible sideroblastic anemia, have been reported.
tetrathiomolybdate (TM) -
This drug acts in a different way in
that it interferes with the uptake of copper from the intestinal tract. As yet,
clinical experiments with the drug are limited.
Like TM, zinc interferes with the uptake of copper from the digestive tract. It
can give rise to side-effects. Besides being an immunosuppressant, zinc can act
as a gastric irritant.
Transplantation (OLT) -
OLT seems to be the only treatment
option for those with acute liver disease or cirrhosis due to Wilson's disease.
Wilson's disease can
be fatal if left untreated.
Prognosis of WD often
depends on the severity of the liver and neurologic diseases and on the
patients' response to various treatments. Usually WD patients with liver
disease do not respond well to treatment. On the other hand, those patients who
present with neurologic symptoms fare much better than those that present with
Journal of hepatology 2012 VOL 56, 671-685