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Clinical features of Wilson disease

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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
61
Stremmel et al. Clinical features
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2):S61atm.amegroups.com
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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
Annals of Translational Medicine, Vol 7, Suppl 2 April 2019 Page 3 of 5
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2):S61atm.amegroups.com
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
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2):S61atm.amegroups.com
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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.
Annals of Translational Medicine, Vol 7, Suppl 2 April 2019 Page 5 of 5
© 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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2. European Association for Study of Liver. EASL Clinical
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4. Eisenbach C, Sieg O, Stremmel W, et al. Diagnostic
criteria for acute liver failure due to Wilson disease. World
J Gastroenterol 2007;13:1711-4.
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disease: a review. Gen Hosp Psychiatry 2014;36:53-62.
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Treasure Island, USA: 2018.
9. Czlonkowska A, Litwin T, Dusek P, et al. Wilson disease.
Nat Rev Dis Primers 2018;4:21.
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
A B
... Wilson's disease earlier named as Wilson's hepatolenticular degeneration has a prevalence of 1:30000 with a much more genetic prevalence, andmean age of presentation is 26.1 ± 17.2 with earlier diagnosis in men [3,4]. Thirty percent patients with the mutation are asymptomatic and are usually detected with family screening [5]. And in symptomatic, half of them present with both hepatic and neurological features and the remaining half present with pure hepatic or neuropsyciatric manifestations [5]. ...
... Thirty percent patients with the mutation are asymptomatic and are usually detected with family screening [5]. And in symptomatic, half of them present with both hepatic and neurological features and the remaining half present with pure hepatic or neuropsyciatric manifestations [5]. ...
... Hemolytic anemia or even fulminant hepatic failure as the initial presentation of Wilson's is frequent reported in young children and adolescents 5 . The bursting of copper laden lysosomes leading to release of large amounts of copper in blood, and as copper is loosely bound to albumin it attacks the RBCs plasma membrane resulting in Coomb's negative hemolytic anemia or sometimes acute hemolytic crisis. ...
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Wilson’s disease is one the rare autosomal recessive disorders of copper metabolism due to mutation in ATP7B gene located in chromosome 13. The mutations of this gene cause accumulation of copper in different tissues such as brain, liver, and eyes. The clinical presentation usually reflects this tissue distribution and varies from asymptomatic patients to those with hepatic or neuro-psychiatric manifestations. Here, we report an interesting case of Wilson’s disease which presented with mild persistent hemolysis leading to pre hepatic and post hepatic jaundice. He also had hepatocellular jaundice due to liver injury.
... Wilson disease is a rare (1:30,000 inhabitants) inherited copper overload disease of the liver due to impaired biliary copper excretion. It affects female as well as male individuals and manifests mostly in late childhood or adolescence (1). It is an autosomal recessive disorder due to mutation of the ATP7B gene located on the long arm of chromosome13 at position 14.3 (2). ...
... After release from mucosal cells copper is transported bound to albumin via portal blood to the liver from where it is extracted by Ctr1. Within hepatocytes the free cytotoxic Cu + is bound after uptake to the Antioxidant protein 1 (Atox1) from where it is handled to ATP7B for translocation to TGN (1). During phases of copper overload, excess Cu + is transiently bound and stored in a complex with metallothionein (1) (Figure 1). ...
... Copper accumulation in the cornea appears as goldenbrown rings around the edge of the eye lenses are called Kayser-Fleischer rings. They do not impair vision (1,20). Copper accumulation in kidneys and heart are rarely observed causing tubulopathy and cardiomyopathy, respectively. ...
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Wilson disease is a copper overload disease treatable with the chelators D-penicillamine and trientine to enhance urinary excretion or with zinc which predominantly inhibits absorption. By lifelong treatment a normal life expectancy and significant improvement of hepatic injury as well as neurologic manifestation is achievable. Here we evaluate the mode of action for effective therapy of Wilson disease. We postulate that there is no quantitative removal of copper from the liver possible. The therapeutic goal is the removal of toxic free copper (non-ceruloplasmin, but albumin bound copper). This is achievable by the induction of metallothionein which is accomplished by chelators and in particular by zinc. For control of therapy the option of a direct measurement of free copper would be preferable over the less reliable calculation of this fraction. A therapeutic challenge is still the full restoration of neurological deficits which can hardly be reached by the available chelators. Whether bis-choline-tetrathiomolybdate as intracellular copper chelator is an option has to be awaited. It is concluded that the goal of actual drug therapy in Wilson disease is the normalization of free copper in serum.
... [1][2][3] Progressive copper accumulation has a negative impact on multiple organs and tissues, including hepatic (acute liver failure, active hepatitis, cirrhosis), neurologic (Parkinson-like symptoms), psychiatric (depression, psychosis), ocular (Kayser-Fleischer corneal rings, cataracts), renal (renal tubular acidosis, urolithiasis, proximal/distal tubular dysfunction, proteinuria), and muscular (rhabdomyolysis, osteoporosis) complications. 4 A recent review reported the prevalence of WD to be approximately 1.5-3.5 per 100,000 individuals across the United States, Europe, and Asia. 5,6 WD affects an equal number of both males and females JOURNAL OF HEALTH ECONOMICS AND OUTCOMES RESEARCH and is found in all ethnic groups and races. ...
... However, in young children, the majority of WD cases are asymptomatic and are usually discovered on familial screening or abnormal liver function test results. 4,13,14 Given that patients often present with hepatic, neurologic, and psychiatric manifestations, management of WD should involve a multispecialty approach. In WD, no new therapeutic options have been introduced in over 50 years. ...
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Background: Wilson's disease (WD) is a rare inherited genetic disorder characterized by the progressive accumulation of copper in the brain, liver, and other major organ systems. To date, there have been no comprehensive studies synthesizing evidence pertaining to the quality of life (QOL) in WD. Objective: We conducted a systematic literature review to identify and synthesize the evidence on QOL in patients with WD. Methods: To address this gap in the literature, we conducted a systematic literature review in MEDLINE and EMBASE to identify observational studies and clinical trials reporting QOL outcomes among people living with WD. Results: A total of 442 publications were identified, 41 publications were eligible for full-text screening, and 7 articles, representing 7 studies, met all inclusion criteria. QOL questionnaires used across studies included the 12-Item Short Form Health Survey Questionnaire (version 1) (SF-12) (n=2), the 36-Item Short Form Health Survey Questionnaire (version 1) (SF-36) (n=3), Global Assessment Scale (GAS) (n=1), and World Health Organization QOL brief questionnaire (WHO-QOL-BREF) (n=1). Overall, the pattern in QOL from most studies demonstrated a worse QOL in WD patients compared with the general population, a deterioration in QOL for patients presenting with neurologic symptoms, and more frequent psychiatric symptoms compared with the ones with hepatic symptoms. Discussion: Although our understanding of the underlying pathophysiology of WD has advanced, and novel therapeutics are on the horizon, our understanding of how WD affects overall QOL remains limited. Evidence from this review demonstrates the substantial heterogeneity in reporting outcomes pertaining to the QOL associated with WD. These differences may be attributable to the fact that QOL is not typically assessed and the lack of a standardized method for assessing QOL in WD. Conclusion: This review demonstrates a need for more up-to-date studies with larger sample sizes to further evaluate QOL in patients with WD. The study also demonstrates the need for a WD-specific instrument to measure the QOL in WD patients.
... W ilson's disease (WD) is an autosomal recessive disorder caused by mutation of the ATP7B gene on chromosome 13 causing altered functioning of a copper-transporting ATPase expressed in hepatocytes and defective metabolism of copper and its accumulation in various tissues of the body. 1 Up to 30% of the affected are asymptomatic at detection by family screening, whereas majority present with hepatic or neuropsychiatric symptoms. 2 Treatment consists of lifelong chelation therapy with D-penicillamine, trientine, or zinc and a copper-free diet along with symptomatic therapy. Untreated, this disease is progressive and may lead to severe morbidity and mortality. ...
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Objectives: Wilson's disease (WD) is a chronic disease caused by altered copper metabolism requiring lifelong therapy. Its long-term and debilitating nature has the potential to affect the quality of life (Qol) of patients as well as their families. Our study aims to assess this impact of the disease on patients and their families. Methods: We conducted a prospective, observational study over 2 years on 73 patients and 73 age-matched controls with 33 children and 40 adults in each group. The Qol of cases and controls was assessed using the PedsQL Generic Core Scales and World Health Organisation Quality of Life BREF (WHOQOL-BREF) for children and adults, respectively. Families of child and adult patients were interviewed using PedsQL Family Impact Module and Family Attitude Scale (FAS), respectively. The data were statistically analyzed. Results: Mean age of the cases was 22.04 ± 11.8 years. Qol scores for both adults and children were worse in cases with neuropsychiatric disease than in those with hepatic disease. For children, the mean scores of overall psychological functioning were lower in cases compared with controls (P = 0.0001). Qol of parents of the patients was significantly lower than those of parents of the controls as was the family functioning (P = 0.0001 and P = 0.016). Family Attitude Scale scores for adults did not differ significantly between cases and controls. Conclusion: The Qol of patients with neuro-WD is worse than that of hepatic disease. The disease impacts the psychological functioning of the children and the Qol of their families, which improves with the duration of the disease. What is known: WD is a long-term, debilitating disease. Patients have to take lifelong treatment with frequent medical visits and often multiple hospitalizations. What is new: WD affects the Qol of not only the patients but also their families. Qol of patients with neuro-WD is worse than that of patients with hepatic disease.
... Chemicals of clinical interests include alcohol (1)(2)(3)(4)(5) and aliphatic halogenated hydrocarbons such as CCl 4 (carbon tetrachloride) (6)(7)(8)(9)(10)(11). In addition, heavy metals are found in excess amounts in the liver of patients with genetic liver diseases such as primary hemochromatosis with excess Review Article on Unresolved Basis Issues in Hepatology of iron (12,13), or Wilson's disease with excess of copper (14,15). Clinically important are also toxic liver diseases caused by herbs leading to herb induced liver Injury (HILI) (16)(17)(18)(19), and drugs presenting as idiosyncratic drug induced liver injury (DILI) (17,(20)(21)(22)(23)(24). ...
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... Etiologies of hypoparathyroidism (HypoPT)[1,8,51,52]. lactic acidosis, and stroke-like syndrome; MTPDS, mitochondrial trifunctional protein deficiency; AIH, autoimmune hepatitis; POF, primary ovarian failure; ACTH, adrenocorticotropic hormone; TIBC, total iron binding capacity; LFT, liver function test; CaSR, calcium-sensing receptor; Mg +2 , magnesium; , leads to; ♦, symbol used as a bullet point. ...
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... This variation comes with over 500 ATP7B mutations (http://www.wilsondisease.med.ualberta.c/databse.asp (accessed on 30 June 2020)) [19][20][21][22]. On top, it suggests the involvement of modifier genes and/or environmental factors that affect the clinical presentation. ...
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Faster, more sensitive, and higher resolution quantitative instrumentation are aiding a deeper understanding of how inorganic chemistry regulates key biological processes. Researchers can now image and quantify metals with subcellular resolution, leading to a vast array of new discoveries in organismal development, pathology, and disease. Metals have recently been implicated in several diseases such as Parkinson's, Alzheimers, ischemic stroke, and colorectal cancer that would not be possible without these advancements. In this review, instead of focusing on instrumentation we focus on recent applications of label-free elemental imaging and quantification and how these tools can lead to a broader understanding of metals role in systems biology and human pathology.
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Background and Objective Wilson disease (WD) is an autosomal recessive inherited disorder of copper metabolism. Chelation of excessive copper is recommended but data on the pharmacokinetics of trientine are limited. The aim of this study was to compare the pharmacokinetics of a new trientine tetrahydrochloride formulation (TETA 4HCl) with those of an established trientine dihydrochloride (TETA 2HCl) salt.MethodsA randomised single-centre crossover study to evaluate the pharmacokinetics, safety and tolerability of two different oral formulations of trientine (TETA 4HCl tablets vs TETA 2HCl capsules) in 23 healthy adult subjects receiving a single dose equivalent to 600 mg of trientine base was performed.ResultsFollowing oral administration, the median time to reach maximum plasma concentration (Tmax) was 2.00 h (TETA 4HCl) and 3.00 h (TETA 2HCl). The rate (maximum plasma concentration [Cmax]) and extent (area under the plasma concentration-time curve from time zero to infinity [AUC0–∞]) of absorption of the active moiety, trientine, were greater (by approximately 68% and 56%, respectively) for TETA 4HCl than for the TETA 2HCl formulation. The two formulations presented a similar terminal elimination rate (λz) and a similar terminal half-life (t½) for trientine. Differences between TETA 4HCl and TETA 2HCl in the levels of the two main mono- and diacetylated metabolites were less than seen for trientine. For both tested formulations, healthy male volunteers demonstrated higher trientine plasma levels but lower mono- and diacetylated metabolite levels compared with females, with no sex differences in terminal half-life (t½) observed. Single oral doses of both formulations were safe and well tolerated.Conclusions Compared with an identical dose of a TETA 2HCl formulation, the TETA 4HCl formulation provided more rapid absorption of trientine and greater systemic exposure in healthy subjects.Clinical Trials Number EudraCT # 2015-002199-25.
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Es ist leicht, einem klar strukturierten Menschen zuzuhören. Was aber, wenn die Geschichte wirr und konfus klingt und man sich als Zuhörer fragen muss: Ist das jetzt wahr oder Fantasie? Und was bedeutet das für die ärztliche Anamnese bei der Frage, ob eine seltene Erkrankung vorliegt?
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Wilson disease (WD) is a potentially treatable, inherited disorder of copper metabolism that is characterized by the pathological accumulation of copper. WD is caused by mutations in ATP7B, which encodes a transmembrane copper-transporting ATPase, leading to impaired copper homeostasis and copper overload in the liver, brain and other organs. The clinical course of WD can vary in the type and severity of symptoms, but progressive liver disease is a common feature. Patients can also present with neurological disorders and psychiatric symptoms. WD is diagnosed using diagnostic algorithms that incorporate clinical symptoms and signs, measures of copper metabolism and DNA analysis of ATP7B. Available treatments include chelation therapy and zinc salts, which reverse copper overload by different mechanisms. Additionally, liver transplantation is indicated in selected cases. New agents, such as tetrathiomolybdate salts, are currently being investigated in clinical trials, and genetic therapies are being tested in animal models. With early diagnosis and treatment, the prognosis is good; however, an important issue is diagnosing patients before the onset of serious symptoms. Advances in screening for WD may therefore bring earlier diagnosis and improvements for patients with WD.
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Wilson's disease can result in fulminant liver failure due to hepatic copper overload. The CD95 system mediates apoptosis and has been demonstrated to be involved in liver disease. In this study CD95 mediated apoptosis was investigated in patients with fulminant hepatic failure in the course of Wilson's disease and in an in vitro model of copper treated human hepatoma cells. In patients, hepatic expression of CD95 and CD95L mRNA and apoptosis were detected. Copper overload in vitro resulted in hepatocytic apoptosis which could be reduced with a neutralizing anti-CD95L antibody. Copper treatment of hepatocytes results in activation of the CD95 system and induction of apoptosis which is operative during the course of hepatic failure in acute Wilson's disease.
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This Clinical Practice Guideline (CPG) has been developed to assist physicians and other healthcare providers in the diagnosis and management of patients with Wilson's disease. The goal is to describe a number of generally accepted approaches for diagnosis, prevention, and treatment of Wilson's disease. Recommendations are based on a systematic literature review in the Medline (PubMed version), Embase (Dialog version), and the Cochrane Library databases using entries from 1966 to 2011. The Grades of Recommendation, Assessment, Development, and Evaluation (GRADE) system used in other EASL CPGs was used and set against the somewhat different grading system used in the AASLD guidelines (Table 1A and B). Unfortunately, there is not a single randomized controlled trial conducted in Wilson's disease which has an optimal design. Thus, it is impossible to assign a high or even a moderate quality of evidence to any of the questions dealt with in these guidelines. The evaluation is mostly based on large case series which have been reported within the last decades.
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To describe the diagnostic criteria for acute liver failure due to Wilson disease (WD), which is an uncommon cause of acute liver failure (ALF). We compared findings of patients presenting with ALF due to WD to those with ALF of other etiologies. Previously described criteria, such as low alkaline phosphatase activity, ratio of low alkaline phosphatase to total bilirubin or ratio of high aspartate aminotransferase (AST) to alanine aminotransferase (ALT), failed to identify patients with ALF due to WD. There were significant differences in low ALT and AST activities (53 +/- 43 vs 1982 +/- 938, P < 0.0001 and 87 +/- 44 vs 2756 +/- 2941, P = 0.037, respectively), low choline esterase activity (1.79 +/- 1.2 vs 4.30 +/- 1.2, P = 0.009), high urine copper concentrations (93.4 +/- 144.0 vs 3.5 +/- 1.8, P = 0.001) and low hemoglobin (7.0 +/- 2.2 vs 12.6 +/- 1.8, P < 0.0001) in patients with ALF caused by WD as compared with other etiologies. Interestingly, 4 of 7 patients with ALF due to WD survived without liver transplantation. In ALF, these criteria can help establish a diagnosis of WD. Where applicable, slit-lamp examination for presence of Kayser-Fleischer rings and liver biopsy for determination of hepatic copper concentration still remain important for the diagnosis of ALF due to WD. The need for liver transplantation should be evaluated carefully as the prognosis is not necessarily fatal.
Article
Wilson disease (WD) is an inherited disorder of hepatic copper metabolism with considerable variation in clinical presentations, the most common ones being liver disease and neuropsychiatric disturbances. This study investigated the clinical presentation in relation to mutations in a large cohort of WD patients. Patients and methods: 1357 patients (702 children, 655 adults; 1172 index patients, 185 siblings, all with a Leipzig score ≥ 4, male/female:679/678) were studied. The age and the symptoms at presentation were used as key phenotypic markers. Index patients were clinically classified either as having hepatic (n=711) or neurologic disease (n=461). 708 (52.8%) patients had a liver biopsy at diagnosis. DNA was sequenced by the Genetic Analyzers ABI Prism 310 (Perkin Elmer) or 3500 (Applied Biosystems). Major findings: 1.Three hundred ninety four different mutation combinations were detected. The most frequent mutation was H1069Q (c.3207C>A; allele frequency: 46.9%), followed by P767P-fs (c.2304dupC; 2.85%), P1134P-fs (c.3402delC; 2.8%), and R969Q (c.2755C>T; 2.18%). 2.There was no correlation between mutations and individual clinical manifestation. 3.There was a gender effect in index patients: hepatic presentation was more common in females (m/f: 328/383) and neurologic presentation in males (259/202; p<0.001). 4.At diagnosis already 39.5% of children/adolescents ( 18) but 58% of adults had cirrhosis. The presence of cirrhosis did not correlate with the genotype. Conclusion: These findings refine and extend our understanding of the natural history and individual spectrum/manifestations of WD. Initially, there is asymptomatic hepatic involvement which may progress and become symptomatic. Neurologic symptoms present many years later. This article is protected by copyright. All rights reserved.
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Wilson disease – can present with such a variety of psychiatric and cognitive symptoms that it has been named the “great masquerader.” Symptoms may include cognitive deficits, impairment of executive function, mood disturbance or psychosis. These impairments may occur in different stages of the disease and with varying intensity in individual patients. This chapter reviews the literature and authors' clinical experiences of the assessment, mechanism, and prevalence of cognitive and psychiatric pathology occurring in Wilson disease. Evidence of pharmacologic and nonpharmacologic treatments is also discussed.
Article
To review the current evidence about psychiatric symptoms in Wilson's disease (WD). We searched Ovid, PsychInfo, CINHAL and PubMed databases from May 1946 to May 2012 using the key words Wilson('s) disease in combination with psychiatry, psychiatric, psychosis, schizophrenia, depression, mania, bipolar, mood, anxiety, personality and behavior. Psychiatric symptoms occur before, concurrent with or after the diagnosis and treatment for WD. Thirty to forty percent of patients have psychiatric manifestations at the time of diagnosis, and 20% had seen a psychiatrist prior to their WD diagnosis. When psychiatric symptoms preceded neurological or hepatic involvement, the average time between the psychiatric symptoms and the diagnosis of WD was 864.3 days. The prevalence of psychiatric disorders in WD patients varies wildly (major depressive disorder, 4-47%; psychosis, 1.4-11.3%). Certain gene mutations of ATP7B may correlate with specific personality traits. Psychiatric manifestations represent a significant part of the clinical presentation of WD and can present at any point in the course of the illness. Psychiatric manifestations occurring without overt hepatic or neurologic involvement may lead to misdiagnosis. A better understanding of the psychiatric presentations in WD may provide insights into the underlying mechanisms of psychiatric disorders.
European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease
European Association for Study of Liver. EASL Clinical Practice Guidelines: Wilson's disease. J Hepatol 2012;56:671-85.
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Pandey N, John S. Kayser-Fleischer Ring. StatPearls. Treasure Island, USA: 2018.
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Czlonkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers 2018;4:21.