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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)
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:
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
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
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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
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
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
Stremmel et al. Clinical features
© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2)
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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.
Albumin CTR1 Apo-CP Cu-CP
Metallothionein (MT)ATOX1
disruption Cellular
Cu to
other organs
physiological condition Wilson disease
(destructive phase)
Wilson disease
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© Annals of Translational Medicine. All rights reserved. Ann Transl Med 2019;7(Suppl 2)
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)
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common in the general population. Rarely visible are lunulae
and gigantism, the reason behind these remains unclear.
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
Arrhythmic-hyperkinetic course
Choreoathetoid dyskinesia
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
Splenomegaly (symptom of portal
hypertension or hemolysis)
Acute hepatic failure
Chronic active hepatitis
Liver cirrhosis with portal hypertension
Brain See Table 3
Disorder of affects and impulses
Cognitive disorder
Behavior disorders
Kidneys Renal tubular acidosis (incl. Fanconi
Proximal and/or distal tubular dysfunction
(amido-aciduria, hyperphosphaturia,
hypercalciuria, glucosuria, hyperuricosuria,
loss of bicarbonate and potassium
Peptiduria, proteinuria
Eyes Kayser-Fleischer corneal rings
Sun flower cataracts
Heart Cardiomyopathy
Muscles/bones Rhabdomyolysis
Degenerative spine disease
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)
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.
Conicts of Interest: The authors have no conicts of interest
to declare.
1. Strand S, Hofmann WJ, Grambihler A, et al. Hepatic
failure and liver cell damage in acute Wilson's disease
involve CD95 (APO-1/Fas) mediated apoptosis. Nat Med
2. European Association for Study of Liver. EASL Clinical
Practice Guidelines: Wilson's disease. J Hepatol
3. Ferenci P, Stremmel W, Czlonkowska A, et al. Age, sex,
but not ATP7B genotype effectively inuences the clinical
phenotype of Wilson disease. Hepatology 2018. [Epub
ahead of print].
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.
5. Morbus Wilson HW. Extrapyramidalmotorische
Störungen. In: Diener HC, Weimar C. editors. Leitlinien
für Diagnostik und Therapie in der Neurologie. Thieme
Verlag, 2012.
6. Zimbrean PC, Schilsky ML. Psychiatric aspects of Wilson
disease: a review. Gen Hosp Psychiatry 2014;36:53-62.
7. Zimbrean P, Seniow J. Cognitive and psychiatric symptoms
in Wilson disease. Handb Clin Neurol 2017;142:121-40.
8. Pandey N, John S. Kayser-Fleischer Ring. StatPearls.
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
... We also detected the presence of brownish Kayser Fleischer rings, more evident in the lower region of the iris bilaterally. Such a semiological sign is due to copper deposition in the Descemet's membrane of the cornea 26 and is present in approximately 100% of neuropsychiatric WD cases 10 . ...
... Psychiatric symptoms are reported by about 30% to 60% of individuals affected by WD 26 . In this case, the disorder for which the patient had been using Fluoxetine was not specified, however the familiar states that at the time of initiation of therapy, he had a depressive mood, anhedonia, and anxiet. ...
We report a rare case of Wilson Disease with neurologic features in a 31-years-old man. This disease consists of a disturbance of copper metabolism secondary to a mutation in the gene responsible for encoding the tissue transporter and the enzyme that incorporates the excess element into bile, generating toxic accumulation in the liver, cornea, and central nervous system. According to his wife, the patient had been undergoing treatment for an unspecified mood disorder. The clinical picture was characterized by depressive mood, anhedonia, and anxiety and for that, he was using Fluoxetine 40mg daily with good clinical response. He had his first seizure episode on December 3, 2021. He progressed with dysarthria, ataxic gait, dystonia of the right-hand flexor muscles, and intermittent urinary incontinence. Marked worsening was observed after diagnosis of COVID19 on February, 2022. At the clinical evaluation on March 24th, the presence of risorius muscle dystonia (risus sardonicus), resting tremor, and Kayser Fleischer rings at slit-lamp examination was also noted. Cerebrospinal fluid exam without abnormalities. Imaging workup revealed signaled alteration in bilateral putamen, midbrain, and pons. Laboratory tests revealed mild impairment of liver function and abdominal ultrasound with no evident abnormalities. Specific tests confirmed the diagnosis (serum copper and 24-hours urine copper levels elevated and reduced serum ceruloplasmin). This case report represents the importance of a detailed neurological clinical evaluation and association of findings with imaging and laboratory workup. It is a rare disease whose epidemiology in Brazil lacks data and complementary tests have reduced specificity. Early diagnosis and treatment have an impact on the neurological prognosis.
... Intact ceruloplasmin regulates iron metabolism and the transport of copper to non-hepatic cells [7,8]. Furthermore, ATP7B is necessary for the excretion of excessive copper into the bile [9,10]. ...
Full-text available
Background: The aim of this study was to demonstrate that both neurological and hepatic symptoms respond to copper chelation therapy in Wilson disease (WD). However, the time course of their recovery is different. Methods: Eighteen patients with neurological WD from a single specialized center who had been listed for liver transplantation during the last ten years and two newly diagnosed homozygous twins were recruited for this retrospective study. The mean duration of conventional treatment was 7.3 years (range: 0.25 to 36.2 years). A custom Wilson disease score with seven motor items, three non-motor items, and 33 biochemical parameters of the blood and urine, as well as the MELD score, was determined at various checkup visits during treatment. These data were extracted from the charts of the patients. Results: Treatment was initiated with severity-dependent doses (≥900 mg) of D-penicillamine (DPA) or triethylene-tetramin-dihydrochloride (TRIEN). The motor score improved in 10 and remained constant in 8 patients. Worsening of neurological symptoms was observed only in two patients who developed comorbidities (myasthenia gravis or hemispheric stroke). The neurological symptoms continuously improved over the years until the majority of patients became only mildly affected. In contrast to this slow recovery of the neurological symptoms, the MELD score and liver enzymes had already started to improve after 1 month and rapidly improved over the next 6 months in 19 patients. The cholinesterase levels continued to increase significantly (p < 0.0074) even further. One patient whose MELD score indicated further progression of liver disease received an orthotopic liver transplantation 3 months after the diagnosis of WD and the onset of DPA treatment. Conclusions: Neurological and hepatic symptoms both respond to copper chelation therapy. For patients with acute liver failure, the first 4 months are critical. This is the time span in which patients have to wait either for a donor organ or until significant improvement has occurred under conventional therapy. For patients with severe neurological symptoms, it is important that they are treated with fairly high doses over several years.
... The clinical manifestation of Wilson's disease varies considerably. However, liver disease and cirrhosis, neuropsychiatric disorders, Kayser-Fleischer rings in Desçemet's corneal membrane, and acute hemolysis episodes associated with acute liver failure are the most prominent characteristics (Stremmel et al., 2019). ...
Full-text available
Wilson’s disease is a disease that results from a genetic disorder that causes copper accumulation. Wilson’s disease has presented challenges for physicians during the last century, but it can be diagnosed and treated over time. Diagnosing Wilson’s disease is challenging for doctors because of its wide range of clinical manifestations and complexity. Studies that can help diagnose Wilson’s disease include a 24-hour copper urine examination and neurological tests, such as a CT scan or MRI, and liver function tests. There is also a scoring system to help medical personnel diagnose this disease. Correct diagnosis and adequate therapy can be provided, such as penicillamine, trientine, zinc, and, most rarely, liver transplantation. It is also necessary to monitor the side effects of treatment and its effectiveness of treatment. When receiving therapy, Wilson’s disease has a better prognosis than if it is not treated.
... The disease is more prevalent in men with a mean age of presentation of 26 years [11]. Most patients with the disease remain asymptomatic throughout their lives, however, symptomatic patients commonly have hepatic or neuropsychiatric complications [12]. The haematological manifestations of the disease include pancytopenia, isolated cell line dysfunction secondary to hypersplenism, and Coombs negative hemolytic anaemia [6]. ...
Full-text available
Hepatitis E virus (HEV) is a single-stranded RNA virus with 20 million cases reported worldwide. Infected individuals may either remain asymptomatic or develop acute or even fulminant hepatitis. HEV has been implicated in causing Acute-on-Chronic Liver Failure (ACLF) among patients with underlying cirrhosis. Among the causes of cirrhosis, Wilson's disease is an identified cause that results in an increased accumulation of copper in the liver, brain, and other organs. It is noted that Coombs negative hemolytic anaemia is also seen in the clinical spectrum of Wilson's disease, however, Coombs positivity has not been documented. We present a case of a young female who had an undiagnosed chronic liver disease (CLD). The patient developed acute decompensation with HEV infection along with Coombs positive hemolytic anaemia. Her autoimmune hepatitis screen was negative, so the patient was worked up for other causes of CLD, which led to a diagnosis of underlying Wilson's disease. The patient was started on penicillamine and zinc acetate. However, during the disease, the patient developed acute decompensation and unfortunately expired before her transplant could take place. Our case documentation is of importance as Coombs positivity in patients with Wilson's disease has not been reported before. Attending physicians should be suspicious of Wilson's disease in a patient with Coombs positive hemolytic anaemia when other causes cannot be identified. It is also important to promptly identify any other cause of CLD to educate patients regarding factors leading to acute decompensation and progression to ACLF.
... Copper is taken up from the gut, intravenously carried to the liver and actively transported into the hepatocytes via the human copper transporter (hCTR/CTR1) [3]. Intracellularly, antioxidant 1 copper chaperones (ATOX1) mediate copper to the P-adenotriphosphatase ATP7B in the trans-Golgi network, which facilitates the incorporation of copper into apo-ceruloplasmin to produce the copper transporting ceruloplasmin [4,5]. Ceruloplasmin intracellularly regulates iron metabolism and therewith the energy supply of the hepatocytes, delivers copper extracellularly to non-hepatic cells and mediates the excretion of copper from hepatocytes into bile [6,7]. ...
Full-text available
The aim of this study was to demonstrate that pseudocholinesterase (CHE) serum level is a useful diagnostic biomarker for untreated Wilson’s disease (WD). Between 2013 and 2019, about 75 patients were referred to the outpatient department of the University of Düsseldorf with suspected Wilson’s disease. In 31 patients with suspected Wilson’s disease (WD-SUS-group), WD was excluded by means of investigations other than analysis of blood and urine. A total of 27 parameters of blood and urine in these 31 patients were compared to those of 20 de novo patients with manifest WD (WD-DEF-group), which parameter showed the highest significance level of difference between the WD-DEF-group and the WD-SUS-group. Thereafter, receiver operating characteristics (ROC-curves) were analyzed to evaluate which parameter showed the largest area under the curve (AUC) to detect WD. Finally, a logistic regression analysis was performed to analyze which combination of parameters allowed the best classification of the 51 patients either into the WD-DEF-group or into the WD-SUS-group. CHE showed the highest significance level for a difference between the WD-DEF- and WD-SUS-group, had the highest AUC, and, in combination with ceruloplasmin, allowed 100% correct classification. Without CHE, no other combination of parameters reached this level of correct classification. After the initiation of treatment, which regularly results in an improvement in CHE, the high diagnostic accuracy of this biomarker was lost. Cholinesterase turns out to be an excellent biomarker for differentiation between untreated de novo patients with manifest WD and heterozygotic gene carriers.
... In case of massive necrosis of hepatocytes, a significant load of copper is released to the bloodstream and causes oxidative stress to cell membranes. 24 Other possible mechanisms include the sodium pump function impairment and the alternation of cell membrane composition. 23 Hemolysis subsides when the pharmacotherapy of WD is introduced, or when the patient undergoes liver transplantation. ...
Full-text available
Anemia is a common finding among patients with liver diseases. Patients who suffer from anemia are at a higher risk of liver function decompensation and hospitalization. It affects significantly their quality of life and contributes to mortality. Anemia is present in 70% of patients with liver cirrhosis and with varying incidence accompanies other liver disorders. As the etiology of anemia in liver diseases is multifactorial, various cases represent different clinical entities. Anemia accompanying hepatic disorders can be broadly divided into several types, such as anemia associated with blood loss, as well as aplastic, hemolytic and micronutrient deficiency anemia. However, it is sometimes difficult to delineate between those types in the clinical practice, as several pathophysiological causes can be present in one patient. It is reported that the most common cause of anemia in liver disease is blood loss and iron deficiency. Still, the incidence of unclear cases reaching over 50% suggests that other types of anemia can be underdiagnosed. This review comprehensively describes less frequent types of anemia associated with liver disease, namely hemolytic and aplastic anemia (AA). Hemolytic anemia can complicate autoimmune liver diseases or be a manifestation of membranopathy of red blood cells, dependent on severe hepatic function impairment or alcoholic liver disease. Aplastic anemia is best known as a sequela of viral hepatitis, but some degree of bone marrow inhibition can complicate virtually all advanced liver diseases.
Wilson disease (WD) is a congenital copper metabolism disorder with various manifestations and can be treated with oral medication. This study examined the factors related to decline in activities of daily living (ADL) in patients with WD as research in this area remains limited. We enrolled 308 patients with WD, including patients who participated in a national survey and those who sought cares at the Department of Pediatrics, Toho University Ohashi Medical Center, from 2016 to 2017. We analyzed the association between ADL decline and factors including age at diagnosis, period from diagnosis to survey, hepatic symptoms, neurological signs, and psychiatric presentation at diagnosis. The relative risks (RRs) for ADL decline were estimated for each factor using multivariate modified Poisson regression analysis. Overall, 97 out of 308 (31.5%) patients experienced ADL decline. After adjusting for explanatory variables, regression analysis revealed that factors significantly associated with ADL decline were a period of ≥20 years from diagnosis to survey (adjusted RR = 2.34, 95% confidence interval [CI]: 1.47-3.74), hepatic symptoms with splenomegaly (adjusted RR = 2.57, 95% CI: 1.26-5.24), mild neurological signs (adjusted RR = 3.20, 95% CI: 1.96-5.23), and severe neurological signs (adjusted RR = 3.63, 95% CI: 2.28-5.77). Neurological signs, hepatic symptoms with splenomegaly, and a period of 20 years from diagnosis to survey are associated with ADL decline. Thus, careful assessment of patients for these factors is necessary, and these findings may guide future efforts to improve patient prognosis.
Full-text available
Unbalanced Cu homeostasis has been suggested to be associated with hematopoietic disease, but the roles of Cu overload in the hematopoietic system and the potential mechanisms are obscure. Here, we report a novel association and the novel potential pathways for Cu overload to induce proliferation defects in zebrafish embryonic hematopoietic stem and progenitor cells (HSPCs) via down-regulating expression of foxm1-cytoskeleton axis, which is conserved from fish to mammals. Mechanistically, we show the direct binding of Cu to transcriptional factors HSF1 and SP1 and that Cu overload induces the cytoplasmic aggregation of proteins HSF1 and SP1. These result in the reduced transcriptional activities of HSF1 and SP1 on their downstream FOXM1 as well as the FOXM1 transcriptional activities on cytoskeletons in HSPCs, which leads to ultimately cell proliferation impairment. These findings unveil the novel linkage of Cu overload with specific signaling transduction as well as the subsequent HSPC proliferation defects.
Wilson disease is one of the uncommon, hereditary, slowly progressing, and autosomal recessive diseases that cause motion disorders. The pathogenesis of Wilson disease is attributed to the accumulation of copper in different parts of body mainly the brain, eyes, liver, etc. due to the mutation taking place in the ATP7B gene. This disease thus leads to dysfunction of liver, neurons, brain, eyes and infertility. Thus, there is a need of proper treatment for this disease. There are numerous treatments available, including penicillamine, zinc, ammonium tetrathiomolybdate, trientine, and combination drugs; however, these treatments have a variety of side effects and poor pharmacokinetics, leading to the approval of trientine salts, of which trientine tetrahydrochloride was found to be an efficient, safe, and drug with few side effects. In this review, various aspects related to the disease and trientine salts have been summarized including the pathogenesis of Wilson disease, treatments of Wilson disease, mechanism of trientine as well as comparative pharmacokinetics with the safety and efficacy of both the salts of trientine. We have also tried to explain the preference of usage of trientine tetrahydrochloride over trientine dihydrochloride with some drugs in clinical trials. Here various factors that lead to treatment failure and consideration of alternate therapies have been discussed. Clinical trials and investigations are still going on over gene therapy and stem cells usage in the treatment of Wilson disease which can be used as an effective treatment in future.
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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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.
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.
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.
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.
  • N Pandey
  • John S Kayser-Fleischer Ring
Pandey N, John S. Kayser-Fleischer Ring. StatPearls. Treasure Island, USA: 2018.
  • A Czlonkowska
  • T Litwin
  • P Dusek
Czlonkowska A, Litwin T, Dusek P, et al. Wilson disease. Nat Rev Dis Primers 2018;4:21.