Comprehensive overview on Wilson disease

Wilson’s disease
In 1912, Samuel Kinnier-Wilson, described a neurological condition with
severe motor (movement) and mental disturbance due to a disorder of
the basal ganglia; this was associated with cirrhosis of the liver.
Perceptively, Wilson developed the hypothesis that abnormalities in
the liver might be caused by 'a morbid agent' (toxin) generated within a
cirrhotic liver.
Etiology & Epidemiology:
Wilson’s disease affects between 1 in 30 000 and 1 in 100 000
individuals. It occurs in 15 to 30 per million live births. Over 300
mutations have been identified, the, most frequent being His 1069Gly
(H1069Q), found in approximately 50% of Caucasian patients;
compound heterozygotes are common. This mutation is rare in India
and Asia. It occurs worldwide, particularly in countries where
consanguinity is common. A higher incidence has been noted in Jews of
Eastern Europe, inhabitants of Southern Italy, Arabs, Japanese, Chinese,
and Indians, where the frequency may increase to 60 per million births.

Wilson’s disease (hepatolenticular degeneration) is an important
autosomal recessive disorder of copper metabolism caused by a variety
of mutations in the ATP7B gene on chromosome 13.
Copper homeostasis
Copper play a vital role in mitochondrial energy generation, melanin
formation, and cross-linking of collagen and elastin .Total body copper
is in the range of 50 to 150 mg, of which some 8 per cent is found in the
liver. Neonatal and fetal liver tissue tolerate much higher quantities
than does the adult liver, where copper is stored within lysosomes in
association with metallothionein. Copper (2–5 mg daily) absorbed from
the diet is transported loosely bound to albumin. This accounts for
about 10 per cent of circulating copper. Net uptake of copper (around
40–60 per cent) reflects its differential binding to low molecular weight

ligands present in saliva, gastric and duodenal juice, and high molecular
weight ligands present in bile. The regulatory mechanisms involved in
intestinal copper transport are still unknown, although binding occurs
to two cytosolic proteins, one similar to superoxide dismutase and
metallothionein. Metallothionein and active transport of copper–amino
acid complexes are involved in absorption but maintenance of copper
homeostasis depends uniquely on its excretion in bile (1.5–1.7 mg/day);
only about 0.7 µg/day is normally excreted in the urine. Any
interruption in the secretion of bile leads to accumulation of copper in
the liver.
Copper overload or toxicity
Chronic copper toxicity in man occurs in two major forms:
1. A primary (inherited) form, where copper accumulates in and
damages the liver initially, and later the nervous system and other
tissues, giving rise to hepatolenticular degeneration or Wilson's disease.
2. A secondary (acquired) form, where copper accumulates in similar
amounts to Wilson's disease as a consequence of cholestasis, due
either to biliary atresia or Indian childhood cirrhosis (congenital) or
primary biliary cirrhosis (acquired). In chronic active hepatitis, lesser
amounts of accumulated copper exacerbate pre-existing hepatocyte
injury.

Pathophysiology
Normally, dietary copper is absorbed from the stomach and proximal
small intestine and is rapidly taken into the liver, where it is stored and
incorporated into caeruloplasmin, which is secreted into the blood. The
accumulation of excessive copper in the body is ultimately prevented
by its excretion, the most important route being via bile. In Wilson’s
disease, there is almost always a failure of synthesis of caeruloplasmin;
however, some 5% of patients have a normal circulating caeruloplasmin
concentration and this is not the primary pathogenic defect. The
amount of copper in the body at birth is normal but thereafter it
increases steadily; the organs most affected are the liver, basal ganglia
of the brain, eyes, kidneys and skeleton. The ATP7B gene encodes a
member of the copper-transporting P-type adenosine tri phosphatase
family, which functions to export copper from various cell types. At
least 200 different mutation shave been described. Most cases are
compound heterozygotes with two different mutations in ATP7B.
Attempts to correlate the genotype with the mode of presentation and
clinical course have not shown any consistent patterns. The large
number of culprit mutations means that, in contrast to
hemochromatosis, genetic diagnosis is not routine in Wilson’s disease,
although it may have a role in screening families following identification
of the genotype in an index patient. The basal ganglia are damaged and

show cavitation, the kidneys show tubular degeneration, and erosions
are seen in bones. It shows functional homology with the Menkes'
disease gene. Both genes are predicted to encode copper-transporting
membrane p-type ATPases, with characteristic motifs and homology
with the heavy-metal transporting ATPases found in bacteria and yeast.
Sequence analysis of cDNA predicts that the Wilson's disease protein
(ATP7B) has specific metal-binding domains, an ATP-binding domain, a
cation channel, and a phosphorylation region which is involved in
energy transduction from ATP hydrolysis to copper (cation) transport.

Clinical presentation
Wilson's disease may present in childhood, adolescence, or early
adulthood. Symptoms and signs may be clinically undetectable under 5
years of age, and few present after the age of 35 years, although
diagnosis over 55 years has been reported. In 90 per cent of patients,
the disease presents with juvenile hepatic disease or with
neurological/psychiatric manifestations. In large studies of Wilson's
disease patients, initial manifestations were hepatic (40 per cent);
neurological (30 percent); psychiatric (10 per cent); hematological (12
per cent); and renal (1 per cent). 25 per cent of patients have two or
more organs involved (usually liver and brain) at the initial assessment.
Symptoms usually arise between the ages of 5 and 45 years. Hepatic
disease occurs predominantly in childhood and early adolescence,
although it can present in adults in their fifties. Neurological damage
causes basal ganglion syndromes and dementia, which tends to present
in later adolescence. These features can occur alone or simultaneously.
Other manifestations include renal tubular damage and osteoporosis,
but these are rarely presenting features.

Haemolytic
During the early period (neonatal to under 5 years of age), copper may
accumulate in the liver without clinical signs and excess copper in red
cells may present as acute haemolysis or as chronic haemolytic
anaemia.

Liver disease
Episodes of acute hepatitis, sometimes recurrent, can occur, especially
in children, and may progress to fulminant liver failure. The latter is
characterized by the liberation of free copper into the blood stream,
causing massive hemolysis and renal tubulepathy. Chronic hepatitis can
also develop insidiously and eventually present with established
cirrhosis; liver failure and portal hypertension may supervene. Hepatic
presentation of Wilson's disease usually occurs at 8 to 12 years. Acute
hepatitis, chronic hepatitis/cirrhosis, and fulminant hepatic failure are
the three principal patterns of liver disease. Before puberty, symptoms
and signs of hepatic dysfunction are common and may mimic acute
hepatitis. A diagnosis of Wilson's disease should be considered if these
features coincide with abdominal pain and hemolysis, or in children
with hepatomegaly, increased serum transaminases, and a fatty liver.
Five to thirty per cent of patients with Wilson's disease present with
chronic liver damage which progresses to cirrhosis. In the early stages,
patients are vaguely unwell but later develop more specific features of
liver dysfunction such as nausea, easy bruising/bleeding, fluid
retention, and jaundice. Portal hypertension develops with progressive
hepatic insufficiency, splenomegaly, gastro-esophageal varices, and
ascites. In adolescents and older patients, splenomegaly should always
raise the diagnosis of portal hypertension and liver disease. A minority

of patients present with fulminant hepatitis, encephalopathy, and
coagulopathy. Hepatocellular carcinoma is rare in the cirrhosis of
Wilson's disease, unlike hemochromatosis. The possibility of Wilson’s
disease should be considered in any patient under the age of 40
presenting with recurrent acute hepatitis or chronic liver disease of
unknown cause, especially when this is accompanied by hemolysis.
Neurological disease
Neurological presentation usually occurs in older patients, between
ages 14 and 40 years and are of two general patterns, movement
disorders or rigid dystonia. Symptoms may be acute or chronic in onset
and rapidly progressive. In all patients there is some degree of liver
damage or cirrhosis. A common presentation in adolescence is with the
insidious onset of dysarthria, deteriorating physical performance at
school, with clumsiness in using a knife and fork or chopsticks,
deterioration in handwriting, and in physical performance at sport.
Early physical signs include flexion–extension tremor of the hands,
becoming a parkinsonian 'bat's wing' or intention type; abnormal
movements become more obvious, with grimacing and choreiform
movements. Orolaryngeal dysphagia and sialorrhoea are associated
with hypokinesia. Later features include spasticity, rigidity of limbs and
neck muscles, and convulsions, which may occur as a presenting sign or

on commencement of treatment. Involuntary movement disorders
respond to treatment, unlike the spastic-tonic features which mimic
Parkinson's disease. Cognitive and sensory functions are usually
preserved until a late stage. Unusual clumsiness for age may be an early
symptom. Neurological disease typically develops after the onset of
liver disease and can be prevented by effective treatment started
following diagnosis in the liver disease phase. This increases the
importance of diagnosis in the liver phase beyond just allowing
effective management of liver disease. As the disease progresses, the
"classic syndrome" evolves: dysphagia and drooling, rigidity and
slowness of movements of the limbs; flexed limb postures; fixity of
facial muscles with mouth constantly agape, giving an appearance of
grinning or a "vacuous smile"; dysarthria or virtual anarthria (bulbar
extrapyramidal syndrome); and a tremor in repose that increases when
the limbs are outstretched to a coarse, "wing-beating" movement.
Slowed saccadic eye movements and limitation of up gaze are also
characteristic. A notable feature is the tendency for the motor
disorders to be concentrated in the bulbar musculature and to spread
caudally. Thus, the syndrome differs from classic Parkinsonism. Usually
elements of cerebellar ataxia and intention tremor of variable degree
are added at some stage of the disease. Approximately 6 percent of
patients develop seizures (Dening et al). Gradually the disability

increases because of increasing rigidity and tremor. The patient
becomes mute, immobile, extremely rigid, dystonic, and slowed
mentally, the latter usually being a late and variable effect.
Psychiatric
About 60 per cent of patients with neurological features also show
evidence of behavioral or psychiatric disorders caused by excess
cerebral copper. Adolescents may present with a falloff in intellectual
ability at school and/or with truancy. About 20 per cent of patients
present with early psychiatric symptoms. Presentations vary from
depression, phobias, and compulsive disorders to aggressive and
antisocial behavior. In older patients, anxiety states, intellectual
deterioration, and memory loss are more common. These are
important to recognize since otherwise the patient may be placed
solely in mental health care rather than in the joint care of a
neurologist, psychiatrist, and physician who will offer specific therapy.

Kaiser–Fleischer rings
These constitute the most important single clinical clue to the diagnosis
and can be seen in 60% of adults with Wilson’s disease (less often in
children but almost always in neurological) . It is caused by copper
deposition in Descemet's membrane in the cornea. It appears as
a greenish-brown pigment at the corneo-scleral junction and
frequently requires slit-lamp examination for identification. Similar
appearances have been noticed in cryptogenic cirrhosis and with
prolonged cholestasis. Rarely, the posterior membrane of the lens is
involved, producing the appearance of a sunflower cataract.

Fig: Sunflower Cataract
Renal
Renal tubular acidosis due to damage by copper in the proximal and/or
distal tubules is not uncommon. Aminoaciduria and nephrolithiasis may
also occur. Osteomalacia and vitamin D-resistant rickets may result
from tubular loss of phosphate.
Joints
Skeletal abnormalities, particularly early osteoarthritis of the spine
(Scheuermann's disease), polyarthritis, hypermobile joints, and
chondromalacia patellae are recognized features. In the very disabled
patient with neurological disease, hypokinesia may lead to flexion
contractures.

Dermatological
Rarely, the skin may be hyperpigmented, appearing slightly grey with a
bluish appearance of the lunulae of the nails. Long-standing copper
excess may increase skin elasticity.
Cardiac/skeletal muscle
Cardiac abnormalities occur rarely, with cardiac hypertrophy associated
with interstitial fibrosis, small vessel sclerosis and perivascular
myocarditis, and rarely cardiomyopathy, which may lead to congestive
cardiac failure. Copper-induced rhabdomyolysis has also been
described.
Endocrine disturbances
Endocrine disturbances occur as a result of liver dysfunction (for
example, gynaecomastia in men). Women with cirrhosis and copper
toxicity have an increased frequency of abortion, stillbirth, premature
delivery, and menstrual disturbance. Once chelation therapy has
reduced the copper overload, successful pregnancies occur and
chelating agents do not appear to harm the fetus or cause fetal copper
deficiency. Copper may also injure other endocrine organs (e.g. causing
hypoparathyroidism).

Investigations
General investigations
Hematological investigations, such as a full blood count and
haptoglobin, detect anemia and hemolysis; mean corpuscular volume,
prothrombin time, and clotting studies detect malfunction of the liver.
Biochemical investigations will provide additional information. These
include increased serum transaminases (altered liver cell turnover) and
reduced albumin and urea (disturbed hepatocellular function).
Measurement of autoantibody titres (e.g. antimitochondrial antibody)
are important to exclude primary biliary cirrhosis.
Specific investigations
•Serum copper and caeruloplasmin are usually reduced but can be
normal. Hypocaeruloplasminaemia and acaeruloplasminaemia do not
always indicate Wilson's disease. The normal neonatal liver mimics the
Wilson's disease patient, with low or absent plasma caeruloplasmin and
high hepatic copper concentration; synthesis and secretion of
caeruloplasmin to the plasma start during the first 3 to 6 months of life
and hepatic copper concentrations decrease within the first 2 years of
life. Caeruloplasmin will also be reduced in protein malnourished
states, reduced protein synthesis due to liver disease, protein loss due
to the nephrotic syndrome, or a protein-losing enteropathy. Conversely

hyper caeruloplasminaemia occurs as an acute phase protein reactant
in acute inflammation, infection, pregnancy, and after oestrogen
administration. This may increase previously low plasma
caeruloplasmin concentrations to within the normal range.
• Urinary copper is usually increased,100–1000 µg/24 h(1.6–
16 µmol) ; normal levels <40 µg (0.6 µmol). Increased urinary copper
may also occur in other liver diseases such as chronic active hepatitis
and primary biliary cirrhosis. However, an increased urine copper in
association with a low caeruloplasmin indicates Wilson's disease; the
presymptomatic patient may still have a normal urinary copper
excretion. Measurement of urine copper excretion is also important in
monitoring the effects of chelating therapy where, early in treatment,
urine levels may rise to 2000 µg/24 h and fall to less than 100 µg/24 h
as the copper overload is reduced. Special care is needed when
collecting urine samples to avoid contamination, and copper-free
containers are required for the collection. Provocation of urine copper
excretion by giving penicillamine (500 mg orally) may be helpful in
patients where the basal urinary copper is equivocal, and to assess the
response of the Wilson's disease patient to treatment with chelating
agents.

• Liver biopsy aids diagnosis, which depends on measurement
of the amount of copper in the liver (>250 µg/g dry weight),
although high levels of copper are also found in the liver in
chronic cholestasis. Normal hepatic copper concentrations (15–55
µg/g dry weight of liver) can be measured by spectrophotometric assay,
by atomic absorption spectrophotometry, or by neutron activation
analysis. Liver biopsy allows measurement of liver copper concentration
as well as histological assessment. In children or in the presence of
significant liver disease (for example associated with coagulopathy), a
trans jugular liver biopsy may need to be considered. In untreated
Wilson's disease patients, the hepatic copper concentration is greater
than 250 µg/g dry weight, and in heterozygotes, the concentration
range is between 55 and 250 µg/g dry weight. Increased hepatic copper
concentrations also occur in secondary copper overload conditions such
as Indian childhood cirrhosis, primary biliary cirrhosis, sclerosing
cholangitis, and chronic active hepatitis. These can be readily
distinguished from Wilson's disease on clinical, biochemical, and
histological grounds. Normal hepatic copper concentration excludes
Wilson's disease in an untreated patient.

Radiocopper studies
Incorporation of orally administered radiocopper (64Cu, 67Cu, or 65Cu)
into caeruloplasmin at 1, 2, 3, and 48 h distinguishes clearly between
normal patients and those with Wilson's disease, where little or no
radiocopper is incorporated into the newly-synthesized caeruloplasmin.
Radiological imaging
Computer-assisted tomography and magnetic resonance imaging of the
liver do not help in the specific diagnosis of Wilson's disease, although
these imaging techniques will also detect non-specific associations of
Wilson's disease such as splenomegaly and abnormalities in hepatic
parenchyma. Central nervous system imaging with computer-assisted
tomography or MRI demonstrate generalized cerebral atrophy and
abnormalities in the basal ganglia.

Screening of family members
It is important that all first-degree relatives are screened for Wilson's
disease once the diagnosis has been confirmed in the index patient.
This is an essential part of the management of any patient with
Wilson's disease. Screening of children should be after 3 years of age. It
should include a history, clinical examination, slit-lamp examination of
the eyes, liver enzyme and function tests, and serum caeruloplasmin
concentration. If the results are suggestive of Wilson's disease, liver

biopsy and a quantitative measurement of hepatic copper should
follow (or radiocopper studies where liver biopsy is contraindicated).
Molecular tests
The diagnosis of Wilson's disease should be made on the basis of the
clinical presentation, biochemical tests, and confirmed by DNA testing
in patients with a high index of suspicion of the disease. Analysis of
DNA from whole blood may be carried out to detect the common
mutation H1069Q or, in Oriental populations, mutation H714Q. Most
patients are compound heterozygotes carrying two mutations for the
Wilson's disease gene. If the common mutations are not present, each
of 21 exons in the gene must be screened by single strand
conformational polymorphism (SSCP) or complete sequencing.
Currently, this can only be undertaken in genetic units interested in
Wilson's disease, and is not available for screening the general
population. As methods for mutation detection improve, screening for
this disease may become more practical. Western blotting of
caeruloplasmin isoforms obtained from whole blood or dried blood
spots may be another, more simple, way of screening for Wilson's
disease in the neonate and children over the age of 2 years.

Management
The management of Wilson's disease involves the general care of any
patient with liver disease and anemia, and investigation of the family
and siblings, as well as specific therapy.
Diet
Strict dietary restriction of copper is not practical, but Wilson's disease
patients should know which foods are high in copper. These include
chocolate, liver, nuts, mushrooms, legumes, and shellfish. In addition,
many Chinese dishes are high in copper and Oriental Wilson's disease
patients and vegetarians will need special dietary advice. However,
reducing copper in the diet is only an adjunct to the main
pharmacological therapy.
• Lifetime treatment with penicillamine, 1–1.5 g daily,is
effective in chelating copper. If treatment is started early,
clinical and biochemical improvement can occur. Urinary
copper levels should be monitored and the drug dose
adjusted downwards after 2–3 years. Serious side-effects of
the drug occur in 10% and include skin rashes, leucopenia, skin
changes and renal damage.

• Trientine (1.2–1.8 g/day) and zinc acetate (150 mg/day) are used
as maintenance therapy and for asymptomatic cases. All
siblings and children of patients should be screened (ATP7B
mutation analysis is useful) and treatment with zinc is given, even
in the asymptomatic if there is evidence of copper accumulation.
A diet low in copper (i.e. excluding chocolate and peanuts) is
advised.
Prognosis
Early diagnosis and effective treatment have improved the outlook.
Neurological damage is, however, permanent. Acute hepatic failure or
decompensated cirrhosis should be treated by liver transplantation.
Non-compliant patients who discontinue treatment may relapse rapidly
and die; they are refractory to reversal of copper overload on restarting
chelation therapy. In these patients, only liver transplantation would
improve their prognosis.
.

Penicillamine-induced Elastosis Perforans Serpiginosa and
Cutis Laxa in a Patient with Wilson's Disease
.
INTRODUCTION
Elastosis perforans serpiginosa (EPS) is a rare reactive perforating dermatosis that
is characterized by the transepidermal elimination of abnormal elastic fibers1
.
Although D-penicillamine appears to be a clear trigger for EPS2
, penicillamine-
induced EPS has been rarely reported. Penicillamine is a copperchelator that is used
at high dosages for patients with Wilson's disease, and the cutaneous reactions to
this drug can be classified into three groups:hypersensitivity reactions, autoimmune
conditions and a spectrum of cutaneous elastotic and collagen disorders3
. The third
group includes pseudoxanthoma elasticum (PXE),EPS, cutis laxa and
anectoderma4,5
. They may be caused by penicillamine affecting the function of
copper-dependent lysyl oxidase, which is an enzyme involved in crosslinking
between elastin molecules6
.
Herein we report a case illustrating the clinical and histological findings of EPS and
cutis laxa in a patient who was on a long-term high-dose penicillamine for Wilson's
disease. The combination of EPS and cutis laxa induced by penicillamine has rarely
been reported7
and we report the first such case in Korea.
CASE REPORT
A 34-year-old man, who had been treated with D-penicillamine for 20 years for
Wilson's disease, visited the clinic for progressive cutaneous lesions of the neck that
he'd had for the past1 year. He had been taking penicillamine at a doseof500~1,250
mg daily for 20 years since 14 years of age. He had not shown any cutaneous side

effects during the early period of penicillamine intake. However, 2 years previously,
the skin folds over both elbows and knees started to become markedly loose (Fig.
1). But, the lesions had not been evaluated or treated at that time.
Fig. 1
Marked loose folds of skin around the elbow.
In 2009, he came to see us with new lesions on the neck that had been present for
the previous 1 year. Clinical examination revealed multiple match head-sized
keratotic papules on an annular erythematous base on the nape and lateral neck (Fig.
2). A 3-mm punch biopsy specimen from a papule on the neck demonstrated a
perforating channel from the dermis through the epidermis with a surrounding
inflammatory infiltrate and multinucleate giant cells (Fig. 3). Verhoeff-van Gieson
staining of the specimen revealed abnormal elastic fibers in the upper dermis and
transepidermal elimination of those abnormal elastic fibers (Fig. 4A). And the
'bramble-bush' appearance that means thickened elastic bundles with prominent
lateral protrusions is well shown (Fig. 4B).

Fig. 2
Multiple match head-sized keratotic papules on the annular erythematous base on the neck.
Fig. 3A perforating channel from the dermis through the epidermis with a surrounding inflammatory
infiltrate and multinucleate giant cells (H&E,×100).

Fig. 4(A) Abnormal elastic fibers in the upper dermis showing transepidermal elimination (Verhoeff-van
Gieson, ×100). (B) The "bramble bush" appearance of elastic fibers (Verhoeff-van Gieson, ×400).
According to the clinical and histological findings of the patient, we diagnosed him
as having cutis laxa and elastosis perforans induced by penicillamine. After a
consultation with the patient's neurologist, the penicillamine was discontinued and
trientine dihydrochloride, an alternative copperchelator, was commenced. We first
used a CO2 laser to resurface the lesions. Thereafter, we advised him to use topical
tretinoin 0.025% cream and the lesions showed partial regression.
DISCUSSION
Penicillamine is an efficient copper chelatorthat is used for the treatment of Wilson's
disease, cystinuria, rheumatoid arthritis, scleroderma and primitive biliary cirrhosis8
.
Most of the adverse effects of D-penicillamine are cutaneous and they occurring in
25~50% of patients. These adverse effects can be classified into three groups3
,
including early onsetmorbilliform and urticarial hypersensitivity reactions and later
onset bullous and lupus-like autoimmune reactions9
. The third group of

dermopathies is a spectrum of cutaneous elastotic and collagen disorders3
such as
PXE, EPS, cutis laxa and anectoderma4,5
.
The underlying mechanism for how penicillamine disrupts elastin production or
remodeling remains uncertain. One proposed mechanism involves the copper-
dependent enzyme lysyl oxidase. This enzyme is required for the cross-linkage of
elastic and collagen fibers in the dermis. The indirect inhibition of the enzyme
activity by removal of copper from the tissues by penicillamine causes abnormal
elastic fiber accumulation9
. An alternate or complementary mechanism is direct drug
inhibition of the deamination ofthe lysine residues that are necessary for elastin and
collagen maturation10
.
The clinical features seen in penicillamine-induced EPS and cutis laxa are similar to
those seen in the idiopathic heritable forms of the diseases8
. As illustrated in this
case, EPS is characterized by the development of annular or serpiginous
hyperkeratotic papules, and most frequently on the lateral neck and upper limbs.
The characteristics and specific histological changes of penicillamine-induced
elastic fiber damage are thickened elastic bundles with prominent lateral protrusions
giving the so-called 'bramble-bush' appearance11
. In contrast to the calcification of
the shortened, curled basophilic elastic fibers in the inherited forms of PXE,
calcification of elastic fibers in penicillamine-induced elastosis is considered to be
unusual12
. As was present in this case, a variable degree of granulomatous
inflammation is often observed in the dermis11,12
. Transepidermal elimination of
abnormally large and tortuous eosinophilic 'bramble-bush' elastic fibers is an
additional feature of penicillamine-induced EPS13
.
Many treatment modalities have been described in the medical texts because of the
difficulty to manage this condition and there is no "gold standard" therapy. The

moderately effective treatments include cryotherapy, cellophane tape stripping and
oral isotretinoin. There have been some recent reports of successfuloutcomes after
using tazarotene gel14
and imiquimod cream15
. We have used various methods,
including a CO2 laser to resurface the lesions and a tretinoin cream, butthoseinduced
only a partial resolution of the lesions.
Furthermore, discontinuation of penicillamine therapy does not guarantee the
prevention of further development of the dermatosis. Multiple case reports have
described the abrupt onset or recurrence of EPS months to years after stopping
penicillamine therapy9,14,16
. This is likely related to the cumulative doseand the slow
clearance of the drug with the remaining effects on the elastic tissue9
.
In summary, we report here on a case that illustrates the clinical and histological
characteristics of EPS and cutis laxa in a patient who was on long-term high-dose
penicillamine for Wilson's disease. We hope that this case will help physicians
become aware of the adverse dermatologic effects of long-term penicillamine
therapy.

Comprehensive overview on Wilson disease

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