Aliment Pharmacol Ther 2004; 19: 157165.
Review article: diagnosis and current therapy of Wilsons disease
P. FERENCI
Department of Internal Medicine IV, Gastroenterology and Hepatology, University of Vienna, Austria
CLINICAL PRESENTATIONS
Wilsons 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 Wilsons disease is that no two patients, even
within a family, are ever quite alike. With the increased
awareness of Wilsons disease, patients are being diagnosed
earlier and late consequences of the disease, such
as KayserFleischer rings or severe neurological symptoms,
can be prevented and, in future, may occur less
frequently. Uncommon manifestations of Wilsons
disease include hypercalciuria and nephrocalcinosis,
chondrocalcinosis and osteoarthritis, sunflower cataracts
and cardiac manifestations.
The finding of a KayserFleischer 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.
KayserFleischer rings are present in 95% of
patients with neurological symptoms, in 5060% of
patients without neurological symptoms and in only
10% of asymptomatic siblings.
Most patients with Wilsons 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 KayserFleischer rings. Liver disease may
mimic all forms of common liver conditions, including
asymptomatic transaminasaemia, acute or chronic
hepatitis, fulminant hepatic failure and cirrhosis.
Neuropsychiatric disease
Neurological symptoms usually develop in the midteenage
years or twenties.21 However, there are welldocumented
cases of late (4555 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
Wilsons disease is a progressive movement disorder
characterized by dysarthria, dysphagia, apraxia and a
tremorrigidity 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
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 Wilsons disease is usually
made on the basis of clinical findings and laboratory
abnormalities (see Table 1). No additional tests are
required if KayserFleischer rings are present and/or
serum ceruloplasmin levels are low.24 However, there
are a few well-documented cases of neurological
Wilsons disease without KayserFleischer 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 Wilsons disease. Usually, a combination of various
laboratory parameters is necessary to firmly establish
the diagnosis. KayserFleischer rings may be absent in
up to 50% of patients with Wilsonian liver disease and
in an even higher proportion with fulminant Wilsons
disease. Serum ceruloplasmin may be in the low to
normal range in up to 45% of patients with hepatic
Wilsons disease.27 On the other hand, even a low
ceruloplasmin level is not diagnostic for Wilsons disease
in the absence of KayserFleischer rings. Ceruloplasmin
can be decreased in severely malnourished subjects and
in heterozygous carriers of the Wilsons 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
Wilsons disease, nor is a low level sufficient to make a
diagnosis of Wilsons disease.
Similarly, if someone thinks you need a psych eval...
