Clinical features of Wilson disease

Abstract

Wilson disease (WD) presents often as a chameleon with a plethora of mild and discrete symptoms. As disease of young aged people, the clinical diagnosis is extremely difficult and misdiagnoses are frequent. Tremor, dysarthria and hepatomegaly sometimes suggest alcoholic liver disease which is a disaster for the patients. Due to the only moderate abnormality of liver function tests the disease is underestimated in its severity with a fatal prognosis when not adequately treated. Therefore, it is the challenge to consider WD as diagnosis, particularly in young patients with unclear liver disease, neuropsychiatric disorders or hemolysis.

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© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2):S61atm.amegroups.com
Review Article
Clinical features of Wilson disease
Wolfgang Stremmel1, Uta Merle2, Ralf Weiskirchen3
1Institute of Pharmacy and Molecular Biotechnology, University of Heidelberg, Heidelberg, Germany; 2Department of Gastroenterology and
Hepatology, University Hospital of Heidelberg, Heidelberg, Germany; 3Institute of Molecular Pathobiochemistry, Experimental Gene Therapy and
Clinical Chemistry, RWTH-University Hospital, Aachen, Germany
Contributions: (I) Conception and design: None; (II) Administrative support: None; (III) Provision of study materials or patients: None; (IV)
Collection and assembly of data: None; (V) Data analysis and interpretation: None; (VI) Manuscript writing: All authors; (VII) Final approval of
manuscript: All authors.
Correspondence to: Prof. Dr. Wolfgang Stremmel. Department of Pharmacy and Molecular Biotechnology, University of Heidelberg, Im Neuenheimer
Feld 329, Heidelberg 69120, Germany. Email: wolfgangstremmel@aol.com.
Abstract: Wilson disease (WD) presents often as a chameleon with a plethora of mild and discrete
symptoms. As disease of young aged people, the clinical diagnosis is extremely difficult and misdiagnoses are
frequent. Tremor, dysarthria and hepatomegaly sometimes suggest alcoholic liver disease which is a disaster
for the patients. Due to the only moderate abnormality of liver function tests the disease is underestimated
in its severity with a fatal prognosis when not adequately treated. Therefore, it is the challenge to consider
WD as diagnosis, particularly in young patients with unclear liver disease, neuropsychiatric disorders or
hemolysis.
Keywords: Kayser-Fleischer rings; copper overload; clinical manifestation; diagnosis
Submitted Jan 03, 2019. Accepted for publication Jan 07, 2019.
doi: 10.21037/atm.2019.01.20
View this article at: http://dx.doi.org/10.21037/atm.2019.01.20
A pathogenetic view and natural history
The clinical presentation of Wilson disease (WD) depends
on the natural history of the disorder which reflects the
pathogenesis. However, this is not an entirely elucidated
mechanism. Therefore, we present here only one likely
hypothesis.
Due to the defect/lack of ATP7B as the copper
transporter from cytosol to the trans-Golgi-network (TGN),
copper accumulates within cytoplasm where it is bound to
metallothionein (MT). Although MT synthesis is induced
by copper, space is limited. Consequence is the deposition
within lysosomes as copper aggregates, which is histologically
detectable by Rhodamine staining. From now on, it takes
several years before the storage capacity of the lysosomal
compartment reaches its limits. Then they burst and release
their acidic, copper loaded content to the cytosol, where it
induces—possibly via free radical formation—cellular damage
and even cell death. A fulminant hepatic failure can result,
which was shown to be due to an apoptotic chain reaction (1).
Copper, released from destructed hepatocytes, binds in serum
loosely to albumin from where it is provided to other organs
and tissues causing cell damage. In case of a rapid release of
copper to serum, e.g., by fulminant hepatic failure, it might
cause hemolytic anemia.
Initial clinical presentation and acute hepatic
failure
There is indeed an estimated proportion of 30% of WD
patients who are asymptomatic and are detected mostly
by family screening. It is assumed that they remain in the
pre-destructive phase of copper accumulation (Figure 1).
However, the majority of the patients present with clinical
symptoms. About half of these patients have hepatologic
as well as neurologic manifestations. The remaining half
presents either with simple liver disease or pure neuronal
disorders with a latent liver manifestation. Epidemiologic
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Stremmel et al. Clinical features
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analyses show that in children, adolescents and young
adults, WD is the most common reason for hemolytic
anemia and cirrhosis, despite its rare frequency in the entire
population of 1:30,000 (2).
It is indeed our experience that fulminant hepatic failure
as initial presentation is a frequent event in the young
population of WD. Generally affected are more female than
male patients although in the overall WD patient population
there is an equal gender distribution (3). Hemolytic anemia
and fulminant hepatic failure are due to the proposed burst
of lysosomes overloaded with copper which is accompanied
by release of unbound (free) copper into blood. There it is
only loosely bound to albumin (non-ceruloplasmin-bound
copper) and can attack erythrocyte plasma membranes
resulting in a Coombs-negative hemolysis or finally a
hemolytic crisis. Under these circumstances, the urinary
copper excretion of the “free” copper is high. However,
it has to be considered that acute liver failure is often
associated with elevated urinary copper or alternatively
with kidney failure and anuria (4). Low ceruloplasmin is a
diagnostic hallmark of WD. However, ceruloplasmin may
be in the normal range in hepatic failure because it reacts
as an acute phase reactant. Therefore, this value is not
reliable for diagnosis of WD in an acute setting. Moreover,
coagulation is severely impaired in liver failure, particularly
in WD. Thus, liver biopsies for quantitative determination
of the liver copper content are risky, if coagulation factors
and platelets are not adequately substituted. Genetic testing
as another diagnostic option is not always conclusive
and usually the procedure is time lasting within the
short period of time before death may occur. Therefore,
diagnosis of fulminant WD may be a challenge. It is the
clinical picture which suggests the diagnosis. Typical is the
presentation of a young female patient with deep jaundice
and an unremarkable history. The bilirubin is high (about
50% conjugated/50% unconjugated), whereas alkaline
Figure 1 Pathogenetic view of WD. (A) Absorbed copper binds to albumin for transport via portal blood to hepatocytes, where it enters
through the plasma membrane-localized copper transporter (CTR1). Within the cell it is immediately deposited bound to MT. The so-
called antioxidant protein 1 (ATOX1) serves as chaperone for delivery to the TGN, where ATP7B transports copper into the lumen for
binding to apo-ceruloplasmin (Apo-CP) which as copper-loaded ceruloplasmin (Cu-CP) is excreted to blood (main copper bound protein in
blood). A second vesicular pathway directs copper from the TGN to bile, also mediated by ATP7B. (B) In WD ATP7B is lacking prohibiting
TGN directed transfer of copper to ceruloplasmin and bile. Consequently, copper is intermediately accumulated in the stimulated MT pool,
from where it is deposited in lysosomes. (C) In the destructive phase the copper-loading capacity of lysosomes is exceeded. They burst and
release there acidic, free copper-loaded content to cytosol which results in cellular damage and nally cell death. This causes the release of
cellular free copper to blood. It is bound loosely to albumin and delivered to other organs, particularly to the brain. There cellular damage
occurs via free radical injury. WD, Wilson disease; TGN, trans-Golgi-network.
Blood
TGN
Lysosome
Bile
Albumin CTR1 Apo-CP Cu-CP
Cu-MT ATP7B
Cu
Metallothionein (MT)ATOX1
Cu
aggregates
Lysosome
disruption Cellular
damage
Cu to
other organs
Normal
physiological condition Wilson disease
(destructive phase)
Wilson disease
A B C

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phosphatase is surprisingly low in some, but not all cases (4).
Transaminases are only marginally elevated (AST > ALT).
Despite severely impaired coagulation as sign of organ
failure, hepatic encephalopathy is only seen in very late
stages of hepatic decompensation. Hemolytic anemia is
another frequent finding (Table 1). For fulminant hepatic
failure a high-urgency liver transplantation is required.
Fortunately, the outcome of liver transplantation is very
favorable, copper metabolism normalizes quickly after
transplant and most of respective patients show excellent
post liver transplantation survival both at one year and
long-term. The explanted liver reveals—despite the clinical
appearance as acute liver failure—in most cases a cirrhotic
architecture. The elevated liver copper content confirms
nally the diagnosis.
Clinical presentation beyond acute hepatic failure
In most cases (>90% of patients) the redistribution of
hepatic lysosomal copper to cytoplasm is a slow process.
It primarily hits the liver itself through free radical injury
causing cell damage, consequent development of fibrosis
or even cirrhosis. Hepatocellular carcinoma in the rather
young patient population is a rare event. Patients with
WD almost always have a prominent splenomegaly with
concomitant thrombocytopenia. It is in part due to portal
hypertension and in part due to hemolysis.
According to the proposed pathogenesis (Figure 1), there
is a constant spillover of free copper to serum (albumin
bound copper). This is taken up by other organs via the
plasma membrane localized copper transporter CTR1,
causing the clinical manifestation of WD (Table 2). Most
affected is the brain with consequent copper deposition
in the basal ganglia resulting in motoric disturbances
(hepatolenticular degeneration) (Table 3) (5). The fine
motoric skills and coordination are often affected resulting
in micrography, deterioration of writing skills, tremor,
dysphagia, ataxia, nystagmus and frequently speech
disturbance. Later also gross motor skills are in disorder
with choreoathetoidic dyskinesia, dystonia, uncontrolled
movements, spastic contractions, gait abnormalities and
finally disability. In late stages, features are retraction of
upper lip and hypersalivation.
Approximately 30–60% of WD patients show psychiatric
symptoms at presentation (6). Psychiatric manifestations may
include depressive mood, cognitive and affective disorders.
Rarely also psychotic episodes can occur (7). Of note, WD
can be present over years with psychiatric symptoms without
any clinical signs of hepatic or neurologic disease (6).
The deposition in the Descemet’s membrane of the
cornea results in Kayser-Fleischer corneal rings (Figure 2)
or infrequently in sun flower cataracts. Kayser-Fleischer
(KF) rings do not impair the vision. Those deposits are seen
in about 95% of patients with neurologic symptoms and
are considered as pathognomonic for WD. In patients with
primarily hepatic manifestation KF rings are detectable in
only 50% (8). Similar, but less impressive rings are observed
in rare cases in cholestatic liver diseases with moderate
increase of copper in the system due to impaired biliary
excretion (9).
The kidneys develop tubular injury and dysfunction.
Renal tubular acidosis or an aminoaciduria, proteinuria,
hyperuricosuria, hypercalciuria, hyperphosphaturia,
uricosuria and glucosuria were reported. Occasionally,
copper is also accumulated in cardiomyocytes and causes
cardiomyopathy associated with arrhythmias. Osteoporosis
and arthralgia are often registered in WD but are also very
Table 1 Typical features of fulminant hepatic failure in WD
Clinical findings
Females > males
Age below 22 years
Deep jaundice
Unremarkable history
Bleeding tendency
Initially no hepatic encephalopathy
Discrete tremor
Laboratory values
High bilirubin (50% conjugated)
Signs of hemolysis
Low alkaline phosphatase
High international normalized ratio (INR)
Low platelets
Marginally elevated transaminases (AST > ALT)
High urinary copper excretion
Ceruloplasmin only moderately decreased
Genetic testing: homozygous or compound heterozygous
mutations in ATP7B
WD, Wilson disease.

Stremmel et al. Clinical features
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common in the general population. Rarely visible are lunulae
and gigantism, the reason behind these remains unclear.
Conclusions
Clinical features of WD mainly relate to liver and brain.
The development of cirrhosis is common but clinically
apparent only in late stages. Due to the available therapies,
liver disease is not as threatening as it has been until
the 1950’s where it often ended with a fatal prognosis.
Motoric neuropathy is a bigger problem because it is
not always responsive to the decoppering therapies. The
remaining clinical features span many disorders resulting
from copper overload and cell damage of different tissues.
These other manifestations are rare, like renal tubulopathy,
cardiomyopathy or unspecic like osteoporosis or harmless
like Kayser-Fleischer rings. Hemolysis and fulminant
Table 3 Neurologic manifestations in WD
Pseudo-sclerotic course
Tremor (resting, holding, intension)
Scanting dysarthria
Cerebellar ataxia
Nystagmus (“dancing eyes”)
Pseudo-parkinsonic course
Hypo-/bradykinesia
Rigidity
Dysarthria
Tremor
Arrhythmic-hyperkinetic course
Choreoathetoid dyskinesia
Dystonia
Other findings
Writing disorder with micrographia
Dysphagia with pseudohypersalivation
Gait disorder, rarely spastic
Rarely epilepsia
WD, Wilson disease.
Table 2 Clinical manifestations in WD
Classification Clinical manifestations
Liver Asymptomatic with normal laboratory values
Asymptomatic with elevation of liver function
tests
Splenomegaly (symptom of portal
hypertension or hemolysis)
Steatosis
Acute hepatic failure
Chronic active hepatitis
Liver cirrhosis with portal hypertension
Brain See Table 3
Psychiatric
manifestation
Disorder of affects and impulses
Cognitive disorder
Behavior disorders
Depression
Psychosis
Kidneys Renal tubular acidosis (incl. Fanconi
syndrome)
Proximal and/or distal tubular dysfunction
(amido-aciduria, hyperphosphaturia,
hypercalciuria, glucosuria, hyperuricosuria,
loss of bicarbonate and potassium
Urolithiasis
Peptiduria, proteinuria
Eyes Kayser-Fleischer corneal rings
Sun flower cataracts
Heart Cardiomyopathy
Arrhythmias
Muscles/bones Rhabdomyolysis
Osteoporosis
Osteomalacia
Degenerative spine disease
Arthritis/arthralgia
Skin Lunulae
Acanthosis nigricans
WD, Wilson disease.

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© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2):S61atm.amegroups.com
hepatic failure are important complications often observed
in young patients as initial symptoms. To consider WD in
these cases can direct the patients to the life-saving therapy
of liver transplantation.
Acknowledgements
None.
Footnote
Conicts of Interest: The authors have no conicts of interest
to declare.
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Figure 2 Kayser-Fleischer rings. (A) One of the most striking clinical signs that appears in WD is the appearance of a brownish-yellow
ring that is visible around the corneo-scleral junction. These rings are named after B. Kayser and B. Fleischer and consist of annular copper
deposits in the Descemet’s membrane; (B) these changes are best detectable in a slit-lamp examination.
Cite this article as: Stremmel W, Merle U, Weiskirchen
R. Clinical features of Wilson disease. Ann Transl Med
2019;7(Suppl 2):S61. doi: 10.21037/atm.2019.01.20
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