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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
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© 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
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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
A B
... Electron microscopy data on the liver of the patient exposed to high amounts of copper were not available [99,101] but have been reported in animal studies as irregularly shaped nuclei, abundant mitochondria, and displayed cristae, and hepatocytes with an inclusion of secondary lysosomes [82]. Prolonged intoxication with exogenous copper has to be differentiated clinically from Wilson disease [66,105,106], a genetic disorder of the liver leading to hepatic copper accumulation [107,108]. ...
... As a copper-storing liver disease caused by inheritable malfunctioning or missing ATP7B, Wilson disease is characterized by a disturbed cellular homeostasis of copper handling primarily in the liver cell [106]. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. ...
... Wilson disease is a multifaceted disorder, difficult to diagnose and often misdiagnosed [106], in part due to physicians' limited knowledge of its clinical features and a low prevalence, ranging from 1:40,000 to 1:50,000 in the general population [116]. In 22.5% of patients, the diagnosis was delayed and was not achieved until three years after the initial symptoms were evident, and the diagnosis was established at a mean age of 20.4 years (SD 10.6, range 4-56) [117]. ...
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Humans are continuously exposed to various heavy metals including copper, iron, cadmium, and arsenic, which were specifically selected for the current analysis because they are among the most frequently encountered environmental mankind and industrial pollutants potentially causing human health hazards and liver injury. So far, these issues were poorly assessed and remained a matter of debate, also due to inconsistent results. The aim of the actual report is to thoroughly analyze the positive as well as negative effects of these four heavy metals on human health. Copper and iron are correctly viewed as pollutant elements essential for maintaining human health because they are part of important enzymes and metabolic pathways. Healthy individuals are prepared through various genetically based mechanisms to maintain cellular copper and iron homeostasis, thereby circumventing or reducing hazardous liver and organ injury due to excessive amounts of these metals continuously entering the human body. In a few humans with gene aberration, however, liver and organ injury may develop because excessively accumulated copper can lead to Wilson disease and substantial iron deposition to hemochromatosis. At the molecular level, toxicities of some heavy metals are traced back to the Haber Weiss and Fenton reactions involving reactive oxygen species formed in the course of oxidative stress. On the other hand, cellular homeostasis for cadmium and arsenic cannot be provided, causing their life-long excessive deposition in the liver and other organs. Consequently, cadmium and arsenic represent health hazards leading to higher disability-adjusted life years and increased mortality rates due to cancer and non-cancer diseases. For unknown reasons, however, liver injury in humans exposed to cadmium and arsenic is rarely observed. In sum, copper and iron are good for the human health of most individuals except for those with Wilson disease or hemochromatosis at risk of liver injury through radical formation, while cadmium and arsenic lack any beneficial effects but rather are potentially hazardous to human health with a focus on increased disability potential and risk for cancer. Primary efforts should focus on reducing the industrial emission of hazardous heavy metals.
... It is also known that prolonged exposure of the liver to high amounts of copper will activate resident hepatic stellate cells to myofibroblasts, which secrete extracellular matrix proteins that generate collagen [64]. This may lead to liver fibrosis and cirrhosis [65,89]. ...
... As a copper-storing liver disease caused by inheritable malfunctioning or missing ATP7B genes, Wilson disease is characterized by disturbed cellular homeostasis of copper handling primarily in the liver cell [89]. If copper export from the liver increases after storage capacity is exceeded, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. ...
... The natural clinical course could include neurologic and/or psychiatric disease. In the absence of a specific treatment, the natural course of Wilson disease is deleterious, and may end up with acute liver failure, cirrhosis, and, rarely, hepatocellular carcinoma [66,89]. ...
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Wilson disease is a genetic disorder of the liver characterized by excess accumulation of copper, which is found ubiquitously on earth and normally enters the human body in small amounts via the food chain. Many interesting disease details were published on the mechanistic steps, such as the generation of reactive oxygen species (ROS) and cuproptosis causing a copper dependent cell death. In the liver of patients with Wilson disease, also, increased iron deposits were found that may lead to iron-related ferroptosis responsible for phospholipid peroxidation within membranes of subcellular organelles. All topics are covered in this review article, in addition to the diagnostic and therapeutic issues of Wilson disease. Excess Cu2+ primarily leads to the generation of reactive oxygen species (ROS), as evidenced by early experimental studies exemplified with the detection of hydroxyl radical formation using the electron spin resonance (ESR) spin-trapping method. The generation of ROS products follows the principles of the Haber–Weiss reaction and the subsequent Fenton reaction leading to copper-related cuproptosis, and is thereby closely connected with ROS. Copper accumulation in the liver is due to impaired biliary excretion of copper caused by the inheritable malfunctioning or missing ATP7B protein. As a result, disturbed cellular homeostasis of copper prevails within the liver. Released from the liver cells due to limited storage capacity, the toxic copper enters the circulation and arrives at other organs, causing local accumulation and cell injury. This explains why copper injures not only the liver, but also the brain, kidneys, eyes, heart, muscles, and bones, explaining the multifaceted clinical features of Wilson disease. Among these are depression, psychosis, dysarthria, ataxia, writing problems, dysphagia, renal tubular dysfunction, Kayser–Fleischer corneal rings, cardiomyopathy, cardiac arrhythmias, rhabdomyolysis, osteoporosis, osteomalacia, arthritis, and arthralgia. In addition, Coombs-negative hemolytic anemia is a key feature of Wilson disease with undetectable serum haptoglobin. The modified Leipzig Scoring System helps diagnose Wilson disease. Patients with Wilson disease are well=treated first-line with copper chelators like D-penicillamine that facilitate the removal of circulating copper bound to albumin and increase in urinary copper excretion. Early chelation therapy improves prognosis. Liver transplantation is an option viewed as ultima ratio in end-stage liver disease with untreatable complications or acute liver failure. Liver transplantation finally may thus be a life-saving approach and curative treatment of the disease by replacing the hepatic gene mutation. In conclusion, Wilson disease is a multifaceted genetic disease representing a molecular and clinical challenge.
... Another ophthalmological manifestation is the much rarer sunflower cataract, visible only on slit-lamp examination [12,13]. These two manifestations do not alter vision [12,14]. ...
... Most cases have cirrhosis with a low-noise, chronic hemolytic anemia, with a few acute episodes that may precede the hepatic or neurological symptomatology by several years [18]. Thrombocytopenia is often found in Wilsonian patients with prominent splenomegaly [14]. It is secondary both to the hypersplenism caused by cirrhosis and to the direct toxicity of copper, which affects megakaryogenesis by causing platelet production abnormalities [13]. ...
... WD is an autosomal recessive disorder caused by pathogenic variants of the ATP7B gene, which encodes a P-type copper transport ATPase, leading to the accumulation of toxic copper concentrations in various organs, particularly the liver and brain [18] . As a result, WD may manifest as hepatic, neurologic, or psychiatric symptoms, or a combination of these [ Table 1] [17,19,20] . ...
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Copper is a trace metal whose absence or deficiency can cause structural and functional alterations that can be corrected by copper administration. Copper excess is associated with significant liver toxicity, such as that seen in Wilson’s disease, which often exhibits liver steatosis and can be managed by copper sequestrants. Copper, due to its ability to either accept or donate electrons, is a cofactor in many physiological redox reactions, playing an essential role in cell energy homeostasis, detoxification of reactive oxygen species, and hepatic immunometabolism. Given these facts, it is reasonable to speculate that copper might be involved in the pathogenesis of liver fibrosis in the setting of metabolic dysfunction-associated fatty liver disease (MASLD). To address this research question, a narrative review of published studies was conducted, spanning from the needs, sources, and toxicity of copper to Menkes and Wilson’s disease. Most epidemiological studies have demonstrated that MASLD is associated with copper deficiency. However, several studies show that MASLD is associated with copper excess and very few conclude that copper is not associated with MASLD. Therefore, the putative pathomechanisms associating both copper excess and deficiency with MASLD development and progression are reviewed. In conclusion, epidemiological and pathogenic data support the notion that well-balanced copper homeostasis is a prerequisite for liver health. Accordingly, both copper excess and deficiency may potentially predispose to liver fibrosis via the development of MASLD. Therefore, studies aimed at restoring normal bodily stores of copper should be tailored according to precision medicine approaches based on the specific features of copper metabolism in individual MASLD patients.
... The homeostatic balance of zinc ions metabolism is essential for the maintenance of normal physiological functions. Zinc deficiency can cause multi-system damage, impacting the proliferation and differentiation of immune cells, resulting in diminished immunity and a higher likelihood of developing immune diseases such as rheumatoid arthritis (Stremmel et al. 2019). Zinc overloading has been confirmed by numerous studies to be strongly correlated with neuronal degenerative diseases, such as Parkinson's disease (PD) and Alzheimer's disease (Szabo 2021;Tanaka et al. 2019;Tang et al. 2023). ...
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Cell death maintains cell morphology and homeostasis during development by removing damaged or obsolete cells. The concentration of metal ions whithin cells is regulated by various intracellular transporters and repositories to maintain dynamic balance. External or internal stimuli might increase the concentration of metal ions, which results in ions overloading. Abnormal accumulation of large amounts of metal ions can lead to disruption of various signaling in the cell, which in turn can produce toxic effects and lead to the occurrence of different types of cell deaths. In order to further study the occurrence and development of metal ions overloading induced cell death, this paper reviewed the regulation of Ca²⁺, Fe³⁺, Cu²⁺ and Zn²⁺ metal ions, and the internal mechanism of cell death induced by overloading. Furthermore, we found that different metal ions possess a synergistic and competitive relationship in the regulation of cell death. And the enhanced level of oxidative stress was present in all the processes of cell death due to metal ions overloading, which possibly due to the combination of factors. Therefore, this review offers a theoretical foundation for the investigation of the toxic effects of metal ions, and presents innovative insights for targeted regulation and therapeutic intervention. Graphical Abstract Highlights • Metal ions overloading disrupts homeostasis, which in turn affects the regulation of cell death. • Metal ions overloading can cause cell death via reactive oxygen species (ROS). • Different metal ions have synergistic and competitive relationships for regulating cell death.
... As an example, cadmium can easily and constantly enter the human body, which cannot provide cadmium homeostasis due to a lack of physiological processes to remove it [6,7]. The conditions are different for iron and copper because they are not useless elements but become essential trace metals for humans, ensuring health and life [7], although copper in excess can lead to the copper-storing liver disorder known as Wilson's disease [8,9], while an overload of iron may cause the hepatic iron-storing disease hemochromatosis [10][11][12][13]. ...
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Hemochromatosis represents clinically one of the most important genetic storage diseases of the liver caused by iron overload, which is to be differentiated from hepatic iron overload due to excessive iron release from erythrocytes in patients with genetic hemolytic disorders. This disorder is under recent mechanistic discussion regarding ferroptosis, reactive oxygen species (ROS), the gut microbiome, and alcohol abuse as a risk factor, which are all topics of this review article. Triggered by released intracellular free iron from ferritin via the autophagic process of ferritinophagy, ferroptosis is involved in hemochromatosis as a specific form of iron-dependent regulated cell death. This develops in the course of mitochondrial injury associated with additional iron accumulation, followed by excessive production of ROS and lipid peroxidation. A low fecal iron content during therapeutic iron depletion reduces colonic inflammation and oxidative stress. In clinical terms, iron is an essential trace element required for human health. Humans cannot synthesize iron and must take it up from iron-containing foods and beverages. Under physiological conditions, healthy individuals allow for iron homeostasis by restricting the extent of intestinal iron depending on realistic demand, avoiding uptake of iron in excess. For this condition, the human body has no chance to adequately compensate through removal. In patients with hemochromatosis, the molecular finetuning of intestinal iron uptake is set off due to mutations in the high-FE2+ (HFE) genes that lead to a lack of hepcidin or resistance on the part of ferroportin to hepcidin binding. This is the major mechanism for the increased iron stores in the body. Hepcidin is a liver-derived peptide, which impairs the release of iron from enterocytes and macrophages by interacting with ferroportin. As a result, iron accumulates in various organs including the liver, which is severely injured and causes the clinically important hemochromatosis. This diagnosis is difficult to establish due to uncharacteristic features. Among these are asthenia, joint pain, arthritis, chondrocalcinosis, diabetes mellitus, hypopituitarism, hypogonadotropic hypogonadism, and cardiopathy. Diagnosis is initially suspected by increased serum levels of ferritin, a non-specific parameter also elevated in inflammatory diseases that must be excluded to be on the safer diagnostic side. Diagnosis is facilitated if ferritin is combined with elevated fasting transferrin saturation, genetic testing, and family screening. Various diagnostic attempts were published as algorithms. However, none of these were based on evidence or quantitative results derived from scored key features as opposed to other known complex diseases. Among these are autoimmune hepatitis (AIH) or drug-induced liver injury (DILI). For both diseases, the scored diagnostic algorithms are used in line with artificial intelligence (AI) principles to ascertain the diagnosis. The first-line therapy of hemochromatosis involves regular and life-long phlebotomy to remove iron from the blood, which improves the prognosis and may prevent the development of end-stage liver disease such as cirrhosis and hepatocellular carcinoma. Liver transplantation is rarely performed, confined to acute liver failure. In conclusion, ferroptosis, ROS, the gut microbiome, and concomitant alcohol abuse play a major contributing role in the development and clinical course of genetic hemochromatosis, which requires early diagnosis and therapy initiation through phlebotomy as a first-line treatment.
... It is possible to calculate a ratio of CuEXC and total serum copper called relative exchangeable copper (REC), which allows to diagnose Wilson's disease with a sensitivity and specificity of nearly 100% when using a cut-off value of > 18.5%. Confirmation can be made through molecular biology study of the ATP7B gene [49][50][51]. ...
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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.
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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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