Wilson's disease
Encyclopedia
Wilson's disease or hepatolenticular degeneration is an autosomal recessive genetic disorder
in which copper
accumulates in tissues
; this manifests as neurological
or psychiatric
symptoms and liver
disease. It is treated with medication
that reduces copper absorption or removes the excess copper from the body, but occasionally a liver transplant
is required.
The condition is due to mutation
s in the Wilson disease protein
(ATP7B) gene
. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carrier
s). If a child inherits the gene from both parents, the child may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson's disease occurs in 1 to 4 per 100,000 people. Wilson's disease is named after Samuel Alexander Kinnier Wilson
(1878–1937), the British neurologist who first described the condition in 1912.
and the brain
, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but haven't received a diagnosis.
) and portal hypertension
. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices
, blood vessels in the esophagus
that may bleed in a life-threatening fashion, as well as enlargement of the spleen
and accumulation of fluid in the abdominal cavity
. On examination, signs of chronic liver disease such as spider naevi
(small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis
of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma
(liver cancer), this risk is relatively very low in Wilson's disease.
About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia
(anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation
) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia
in the bloodstream. When these irritate the brain
, the person develops hepatic encephalopathy
(confusion, coma, seizures and finally life-threatening swelling of the brain
).
(cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonism
features) with or without a typical hand tremor
, masked facial expressions, slurred speech, ataxia
(lack of coordination) or dystonia
(twisting and repetitive movements of part of the body). Seizure
s and migraine
appear to be more common in Wilson's disease. Cognition can also be affected in Wilson's disease. This comes in two, not mutually exclusive, categories, frontal lobe disorder
(may present as impulsivity
, impaired judgement, promiscuity
, apathy
and executive dysfunction
with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction
, without signs of aphasia
, apraxia
or agnosia
). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.
Psychiatric problems due to Wilson's disease may include behavioral changes, depression
, anxiety
and psychosis
. Psychiatric symptoms are commonly seen with the neurological symptoms, they rarely manifest on their own. These symptoms are often not well defined and can be attributed to other causes. Due to this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present.
The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney
, and placenta
. The gene codes for a P-type (cation transport enzyme) ATPase
that transports copper into bile
and incorporates it into ceruloplasmin
. Mutations can be detected in 90%. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Ten per cent have no detectable mutation.
Although 300 mutations of ATP7B have been described, in most populations the cases of Wilson's disease are due to a small number of mutations specific for that population. For instance, in Western populations the H1069Q mutation (replacement of a histidine
by a glutamine
at position 1069 in the protein) is present in 37–63% of cases, while in China this mutation is very uncommon and R778L (arginine
to leucine
at 778) is found more often. Relatively little is known about the relative impact of various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies.
A normal variation in the PRNP
gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE
gene was initially suspected but could not be confirmed.
The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the parents of an individual must carry an affected gene. Most have no family history of the condition. People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.
Wilson's disease is the most common of a group of hereditary diseases that cause copper overload in the liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related to ATP7B mutations: for example, ICC has been linked to mutations in the KRT8
and the KRT18
gene.
Copper is needed by the body for a number of functions, predominantly as a cofactor
for a number of enzymes such as ceruloplasmin, cytochrome c oxidase
, dopamine β-hydroxylase
, superoxide dismutase
and tyrosinase
.
Copper enters the body through the digestive tract
. A transporter protein on the cells of the small bowel
, copper membrane transporter 1
(CMT1), carries copper inside the cells, where some is bound to metallothionein
and part is carried by ATOX1
to an organelle known as the trans-Golgi network
. Here, in response to rising concentrations of copper, an enzyme called ATP7A
releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links copper to ceruloplasmin
and releases it into the bloodstream, as well as removing excess copper by secreting it into bile
. Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and rapidly degraded in the bloodstream.
When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage through a process known as Fenton chemistry
; this damage eventually leads to chronic active hepatitis
, fibrosis
(deposition of connective tissue) and cirrhosis
. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia
, particularly in the putamen
and globus pallidus
(together called the lenticular nucleus); these areas normally participate in the coordination of movement as well as playing a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease.
It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that high levels of free (non-ceruloplasmin
bound) copper have a direct effect on either oxidation of hemoglobin
, inhibition of energy-supplying enzymes in the red blood cell
, or direct damage to the cell membrane
.
Wilson's disease may be suspected on the basis of any of the symptoms mentioned above, or when a close relative has been found to have Wilson's. Most have slightly abnormal liver function tests
such as a raised aspartate transaminase
, alanine transaminase
and bilirubin
level. If the liver damage is significant, albumin
may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time
(a test of coagulation
) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase
levels are relatively low in those with Wilson's-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging
(MRI) of the brain is usually performed; this shows hyperintensities
in the part of the brain called the basal ganglia
in the T2
setting. MRI may also demonstrate the characteristic "face of the giant panda" pattern.
There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin
and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard
or most ideal test is a liver biopsy
.
Levels of ceruloplasmin
are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation
as it is an acute phase protein
. Low ceruloplasmin is also found in Menkes disease
and aceruloplasminemia
, which are related to, but much rarer than Wilson's disease.
The combination of neurological symptoms, Kayser–Fleisher rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed.
and in cholestasis
(any disease obstructing the flow of bile from the liver to the small bowel).
In children, the penicillamine
test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease. This test has not been validated in adults.
. This is assessed microscopically for the degree of steatosis
and cirrhosis
, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 μg
of copper per gram of dried liver tissue confirms Wilson's disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's.
In the earlier stages of the disease, the biopsy typically shows steatosis
(deposition of fatty material), increased glycogen
in the nucleus
, and areas of necrosis
(cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory
cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.
s, nuts
, chocolate
, dried fruit
, liver, and shellfish
.
Generally, penicillamine
is the first treatment used. This binds copper (chelation
) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus
(causing joint pains and a skin rash) or myasthenia
(a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. Intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. A further agent with known activity in Wilson's disease is tetrathiomolybdate. This is still regarded as experimental, although some studies have shown a beneficial effect.
Once all results have returned to normal, zinc
(usually in the form of a zinc acetate
prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein
, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases.
In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol
(British anti-Lewisite) is still occasionally necessary. This treatment is injected intramuscularly
(into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.
People who are asymptomatic
(for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.
, dystonia
, and tremors, as well as preventing the development of contracture
s that can result from dystonia.
is an effective cure for Wilson's disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment, or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.
physician Samuel Alexander Kinnier Wilson
(1878–1937), a neurologist
who described the condition, including the pathological changes in the brain and liver, in 1912. Wilson's work had been predated by, and drew on, reports from German neurologist Carl Westphal
(in 1883), who termed it "pseudosclerosis"; by the British neurologist William Gowers
(in 1888); and by Adolph Strümpell
(in 1898), who noted hepatic cirrhosis. Neuropathologist John Nathaniel Cumings made the link with copper accumulation in both the liver and the brain in 1948. The occurrence of hemolysis was noted in 1967.
Cumings, and simultaneously the New Zealand neurologist Derek Denny-Brown
, working in the United States, first reported effective treatment with metal chelator British anti-Lewisite
in 1951. This treatment had to be injected but was one of the first therapies available in the field of neurology, a field that classically was able to observe and diagnose but had few treatments to offer. The first effective oral chelation agent, penicillamine
, was discovered in 1956 by British neurologist John Walshe. In 1982, Walshe also introduced trientine, and was the first to develop tetrathiomolybdate for clinical use. Zinc acetate therapy initially made its appearance in the Netherlands, where physicians Schouwink and Hoogenraad used it in 1961 and in the 1970s, respectively, but it was further developed later by Brewer and colleagues at the University of Michigan
.
The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and 1990s by several research groups.
s, where it generally only affects the liver. It is due to mutations in the COMMD1
(or MURR1) gene. In non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis), no COMMD1 mutations could be detected to explain their genetic origin.
Genetic disorder
A genetic disorder is an illness caused by abnormalities in genes or chromosomes, especially a condition that is present from before birth. Most genetic disorders are quite rare and affect one person in every several thousands or millions....
in which copper
Copper
Copper is a chemical element with the symbol Cu and atomic number 29. It is a ductile metal with very high thermal and electrical conductivity. Pure copper is soft and malleable; an exposed surface has a reddish-orange tarnish...
accumulates in tissues
Biological tissue
Tissue is a cellular organizational level intermediate between cells and a complete organism. A tissue is an ensemble of cells, not necessarily identical, but from the same origin, that together carry out a specific function. These are called tissues because of their identical functioning...
; this manifests as neurological
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
or psychiatric
Psychiatry
Psychiatry is the medical specialty devoted to the study and treatment of mental disorders. These mental disorders include various affective, behavioural, cognitive and perceptual abnormalities...
symptoms and liver
Liver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
disease. It is treated with medication
Medication
A pharmaceutical drug, also referred to as medicine, medication or medicament, can be loosely defined as any chemical substance intended for use in the medical diagnosis, cure, treatment, or prevention of disease.- Classification :...
that reduces copper absorption or removes the excess copper from the body, but occasionally a liver transplant
Liver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
is required.
The condition is due to mutation
Mutation
In molecular biology and genetics, mutations are changes in a genomic sequence: the DNA sequence of a cell's genome or the DNA or RNA sequence of a virus. They can be defined as sudden and spontaneous changes in the cell. Mutations are caused by radiation, viruses, transposons and mutagenic...
s in the Wilson disease protein
Wilson disease protein
Wilson disease protein is an ATPase that transports copper....
(ATP7B) gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
. A single abnormal copy of the gene is present in 1 in 100 people, who do not develop any symptoms (they are carrier
Genetic carrier
A genetic carrier , is a person or other organism that has inherited a genetic trait or mutation, but who does not display that trait or show symptoms of the disease. They are, however, able to pass the gene onto their offspring, who may then express the gene...
s). If a child inherits the gene from both parents, the child may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older people have been described. Wilson's disease occurs in 1 to 4 per 100,000 people. Wilson's disease is named after Samuel Alexander Kinnier Wilson
Samuel Alexander Kinnier Wilson
Samuel Alexander Kinnier Wilson was a British neurologist who was the first to describe Wilson's disease.-Biography:...
(1878–1937), the British neurologist who first described the condition in 1912.
Signs and symptoms
The main sites of copper accumulation are the liverLiver
The liver is a vital organ present in vertebrates and some other animals. It has a wide range of functions, including detoxification, protein synthesis, and production of biochemicals necessary for digestion...
and the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis. People with liver problems tend to come to medical attention earlier, generally as children or teenagers, than those with neurological and psychiatric symptoms, who tend to be in their twenties or older. Some are identified only because relatives have been diagnosed with Wilson's disease; many of these, when tested, turn out to have been experiencing symptoms of the condition but haven't received a diagnosis.
Liver disease
Liver disease may present as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathyHepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
) and portal hypertension
Portal hypertension
In medicine, portal hypertension is hypertension in the portal vein and its tributaries.It is often defined as a portal pressure gradient of 10 mmHg or greater.-Causes:Causes can be divided into prehepatic, intrahepatic, and posthepatic...
. The latter, a condition in which the pressure in the portal vein is markedly increased, leads to esophageal varices
Esophageal varices
In medicine , esophageal varices are extremely dilated sub-mucosal veins in the lower esophagus...
, blood vessels in the esophagus
Esophagus
The esophagus is an organ in vertebrates which consists of a muscular tube through which food passes from the pharynx to the stomach. During swallowing, food passes from the mouth through the pharynx into the esophagus and travels via peristalsis to the stomach...
that may bleed in a life-threatening fashion, as well as enlargement of the spleen
Splenomegaly
Splenomegaly is an enlargement of the spleen. The spleen usually lies in the left upper quadrant of the human abdomen. It is one of the four cardinal signs of hypersplenism, some reduction in the number of circulating blood cells affecting granulocytes, erythrocytes or platelets in any...
and accumulation of fluid in the abdominal cavity
Ascites
Ascites is a gastroenterological term for an accumulation of fluid in the peritoneal cavity.The medical condition is also known as peritoneal cavity fluid, peritoneal fluid excess, hydroperitoneum or more archaically as abdominal dropsy. Although most commonly due to cirrhosis and severe liver...
. On examination, signs of chronic liver disease such as spider naevi
Spider angioma
A spider angioma is a type of telangiectasis found slightly beneath the skin surface, often containing a central red spot and reddish extensions which radiate outwards like a spider's web...
(small distended blood vessels, usually on the chest) may be observed. Chronic active hepatitis has caused cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
of the liver in most by the time they develop symptoms. While most people with cirrhosis have an increased risk of hepatocellular carcinoma
Hepatocellular carcinoma
Hepatocellular carcinoma is the most common type of liver cancer. Most cases of HCC are secondary to either a viral hepatitide infection or cirrhosis .Compared to other cancers, HCC is quite a rare tumor in the United States...
(liver cancer), this risk is relatively very low in Wilson's disease.
About 5% of all people are diagnosed only when they develop fulminant acute liver failure, often in the context of a hemolytic anemia
Hemolytic anemia
Hemolytic anemia is a form of anemia due to hemolysis, the abnormal breakdown of red blood cells , either in the blood vessels or elsewhere in the human body . It has numerous possible causes, ranging from relatively harmless to life-threatening...
(anemia due to the destruction of red blood cells). This leads to abnormalities in protein production (identified by deranged coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
) and metabolism by the liver. The deranged protein metabolism leads to the accumulation of waste products such as ammonia
Ammonia
Ammonia is a compound of nitrogen and hydrogen with the formula . It is a colourless gas with a characteristic pungent odour. Ammonia contributes significantly to the nutritional needs of terrestrial organisms by serving as a precursor to food and fertilizers. Ammonia, either directly or...
in the bloodstream. When these irritate the brain
Human brain
The human brain has the same general structure as the brains of other mammals, but is over three times larger than the brain of a typical mammal with an equivalent body size. Estimates for the number of neurons in the human brain range from 80 to 120 billion...
, the person develops hepatic encephalopathy
Hepatic encephalopathy
Hepatic encephalopathy is the occurrence of confusion, altered level of consciousness and coma as a result of liver failure. In the advanced stages it is called hepatic coma or coma hepaticum...
(confusion, coma, seizures and finally life-threatening swelling of the brain
Cerebral edema
Cerebral edema or cerebral œdema is an excess accumulation of water in the intracellular or extracellular spaces of the brain.-Vasogenic:Due to a breakdown of tight endothelial junctions which make up the blood-brain barrier...
).
Neuropsychiatric symptoms
About half the people with Wilson's have neurological or psychiatric problems. Most initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms then follow, often in the form of parkinsonismParkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
(cogwheel rigidity, bradykinesia or slowed movements and a lack of balance are the most common parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
features) with or without a typical hand tremor
Tremor
A tremor is an involuntary, somewhat rhythmic, muscle contraction and relaxation involving to-and-fro movements of one or more body parts. It is the most common of all involuntary movements and can affect the hands, arms, eyes, face, head, vocal folds, trunk, and legs. Most tremors occur in the...
, masked facial expressions, slurred speech, ataxia
Ataxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
(lack of coordination) or dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
(twisting and repetitive movements of part of the body). Seizure
Seizure
An epileptic seizure, occasionally referred to as a fit, is defined as a transient symptom of "abnormal excessive or synchronous neuronal activity in the brain". The outward effect can be as dramatic as a wild thrashing movement or as mild as a brief loss of awareness...
s and migraine
Migraine
Migraine is a chronic neurological disorder characterized by moderate to severe headaches, and nausea...
appear to be more common in Wilson's disease. Cognition can also be affected in Wilson's disease. This comes in two, not mutually exclusive, categories, frontal lobe disorder
Frontal lobe disorder
Frontal lobe disorder is an impairment of the frontal lobe that occurs as a result of a number of diseases as well as head trauma. The frontal lobe of the brain plays a key role in higher mental functions such as motivation, planning, social behaviour, and speech production...
(may present as impulsivity
Impulsivity
Impulsivity is a personality trait characterized by the inclination of an individual to initiate behavior without adequate forethought as to the consequences of their actions, acting on the spur of the moment. Eysenck and Eysenck related impulsivity to risk-taking, lack of planning, and making up...
, impaired judgement, promiscuity
Promiscuity
In humans, promiscuity refers to less discriminating casual sex with many sexual partners. The term carries a moral or religious judgement and is viewed in the context of the mainstream social ideal for sexual activity to take place within exclusive committed relationships...
, apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
and executive dysfunction
Executive dysfunction
Executive dysfunction , in psychology , is a disruption to the efficacy of the executive system. It can refer to both neurocognitive deficits and behavioural symptoms...
with poor planning and decision making) and subcortical dementia (may present as slow thinking, memory loss and executive dysfunction
Executive dysfunction
Executive dysfunction , in psychology , is a disruption to the efficacy of the executive system. It can refer to both neurocognitive deficits and behavioural symptoms...
, without signs of aphasia
Aphasia
Aphasia is an impairment of language ability. This class of language disorder ranges from having difficulty remembering words to being completely unable to speak, read, or write....
, apraxia
Apraxia
Apraxia is a disorder caused by damage to specific areas of the cerebrum. Apraxia is characterized by loss of the ability to execute or carry out learned purposeful movements, despite having the desire and the physical ability to perform the movements...
or agnosia
Agnosia
Agnosia is a loss of ability to recognize objects, persons, sounds, shapes, or smells while the specific sense is not defective nor is there any significant memory loss...
). It is suggested that these cognitive involvements are related and closely linked to psychiatric manifestations of the disease.
Psychiatric problems due to Wilson's disease may include behavioral changes, depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, anxiety
Anxiety
Anxiety is a psychological and physiological state characterized by somatic, emotional, cognitive, and behavioral components. The root meaning of the word anxiety is 'to vex or trouble'; in either presence or absence of psychological stress, anxiety can create feelings of fear, worry, uneasiness,...
and psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
. Psychiatric symptoms are commonly seen with the neurological symptoms, they rarely manifest on their own. These symptoms are often not well defined and can be attributed to other causes. Due to this, diagnosis of Wilson's disease is rarely made when only psychiatric symptoms are present.
Other organ systems
Various medical conditions have been linked with copper accumulation in Wilson's disease:- Eyes: Kayser–Fleischer rings (KF rings) may be visible around the iris. They are due to copper deposition in Descemet's membraneDescemet's membraneDescemet's membrane is the basement membrane that lies between the corneal proper substance, also called stroma, and the endothelial layer of the cornea. It is composed of a different kind of collagen than the stroma. The endothelial layer is located at the posterior of the cornea...
of the corneaCorneaThe cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...
. They do not occur in all people and may only be visible on slit lampSlit lampThe slit lamp is an instrument consisting of a high-intensity light source that can be focused to shine a thin sheet of light into the eye. It is used in conjunction with a biomicroscope...
examination. Wilson's disease is also associated with sunflower cataractCataractA cataract is a clouding that develops in the crystalline lens of the eye or in its envelope, varying in degree from slight to complete opacity and obstructing the passage of light...
s, brown or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual loss. KF rings occur in 66% of cases, more often in those with neurological than with liver problems. - Kidneys: renal tubular acidosis, a disorder of bicarbonateBicarbonateIn inorganic chemistry, bicarbonate is an intermediate form in the deprotonation of carbonic acid...
handling by the proximal tubuleProximal tubuleThe proximal tubule is the portion of the duct system of the nephron of the kidney which leads from Bowman's capsule to the loop of Henle.-Structure and appearance:...
s leads to nephrocalcinosisNephrocalcinosisNephrocalcinosis, once known as Albright's calcinosis after Fuller Albright, is a term originally used to describe deposition of calcium salts in the renal parenchyma due to hyperparathyroidism. It is now more commonly used to describe diffuse, fine, renal parenchymal calcification on radiology...
(calcium accumulation in the kidneys), weakening of the bone (due to calcium and phosphate loss) and occasionally aminoaciduriaAminoaciduriaAminoaciduria is the presence of amino acids in the urine. Small amounts of amino acids are also present in normal urine. Increased total urine amino acids may result from metabolic disorders, chronic liver disease or renal disorders. Aminoacidurias can be divided into primary and secondary...
(loss of amino acidAmino acidAmino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
s, needed for protein synthesis). - Heart: cardiomyopathyCardiomyopathyCardiomyopathy, which literally means "heart muscle disease," is the deterioration of the function of the myocardium for any reason. People with cardiomyopathy are often at risk of arrhythmia or sudden cardiac death or both. Cardiomyopathy can often go undetected, making it especially dangerous to...
(weakness of the heart muscle) is a rare but recognized problem in Wilson's disease; it may lead to heart failure (fluid accumulation due to decreased pump function) and cardiac arrhythmias (episodes of irregular and/or abnormally fast or slow heart beat). - Hormones: hypoparathyroidismHypoparathyroidismHypoparathyroidism is decreased function of the parathyroid glands with under production of parathyroid hormone. This can lead to low levels of calcium in the blood, often causing cramping and twitching of muscles or tetany , and several other symptoms...
(failure of the parathyroid glandParathyroid glandThe parathyroid glands are small endocrine glands in the neck that produce parathyroid hormone. Humans usually have four parathyroid glands, which are usually located on the rear surface of the thyroid gland, or, in rare cases, within the thyroid gland itself or in the chest...
s, leading to low calcium levels), infertilityInfertilityInfertility primarily refers to the biological inability of a person to contribute to conception. Infertility may also refer to the state of a woman who is unable to carry a pregnancy to full term...
and habitual abortionHabitual abortionHabitual abortion, recurrent miscarriage or recurrent pregnancy loss is the occurrence of three or more pregnancies that end in miscarriage of the fetus, usually before 20 weeks of gestation...
.
Genetics
The Wilson's disease gene (ATP7B) has been mapped to chromosome 13 (13q14.3) and is expressed primarily in the liver, kidney
Kidney
The kidneys, organs with several functions, serve essential regulatory roles in most animals, including vertebrates and some invertebrates. They are essential in the urinary system and also serve homeostatic functions such as the regulation of electrolytes, maintenance of acid–base balance, and...
, and placenta
Placenta
The placenta is an organ that connects the developing fetus to the uterine wall to allow nutrient uptake, waste elimination, and gas exchange via the mother's blood supply. "True" placentas are a defining characteristic of eutherian or "placental" mammals, but are also found in some snakes and...
. The gene codes for a P-type (cation transport enzyme) ATPase
ATPase
ATPases are a class of enzymes that catalyze the decomposition of adenosine triphosphate into adenosine diphosphate and a free phosphate ion. This dephosphorylation reaction releases energy, which the enzyme harnesses to drive other chemical reactions that would not otherwise occur...
that transports copper into bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
and incorporates it into ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
. Mutations can be detected in 90%. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. Ten per cent have no detectable mutation.
Although 300 mutations of ATP7B have been described, in most populations the cases of Wilson's disease are due to a small number of mutations specific for that population. For instance, in Western populations the H1069Q mutation (replacement of a histidine
Histidine
Histidine Histidine, an essential amino acid, has a positively charged imidazole functional group. It is one of the 22 proteinogenic amino acids. Its codons are CAU and CAC. Histidine was first isolated by German physician Albrecht Kossel in 1896. Histidine is an essential amino acid in humans...
by a glutamine
Glutamine
Glutamine is one of the 20 amino acids encoded by the standard genetic code. It is not recognized as an essential amino acid but may become conditionally essential in certain situations, including intensive athletic training or certain gastrointestinal disorders...
at position 1069 in the protein) is present in 37–63% of cases, while in China this mutation is very uncommon and R778L (arginine
Arginine
Arginine is an α-amino acid. The L-form is one of the 20 most common natural amino acids. At the level of molecular genetics, in the structure of the messenger ribonucleic acid mRNA, CGU, CGC, CGA, CGG, AGA, and AGG, are the triplets of nucleotide bases or codons that codify for arginine during...
to leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
at 778) is found more often. Relatively little is known about the relative impact of various mutations, although the H1069Q mutation seems to predict later onset and predominantly neurological problems, according to some studies.
A normal variation in the PRNP
PRNP
Major prion protein also known as CD230 is a protein that in humans is encoded by the PRNP gene...
gene can modify the course of the disease by delaying the age of onset and affecting the type of symptoms that develop. This gene produces prion protein, which is active in the brain and other tissues and also appears to be involved in transporting copper. A role for the ApoE
Apolipoprotein E
Apolipoprotein E is a class of apolipoprotein found in the chylomicron and IDLs that binds to a specific receptor on liver cells and peripheral cells. It is essential for the normal catabolism of triglyceride-rich lipoprotein constituents.-Function:...
gene was initially suspected but could not be confirmed.
The condition is inherited in an autosomal recessive pattern. In order to inherit it, both of the parents of an individual must carry an affected gene. Most have no family history of the condition. People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.
Wilson's disease is the most common of a group of hereditary diseases that cause copper overload in the liver. All can cause cirrhosis at a young age. The other members of the group are Indian childhood cirrhosis (ICC), endemic Tyrolean infantile cirrhosis and idiopathic copper toxicosis. These are not related to ATP7B mutations: for example, ICC has been linked to mutations in the KRT8
Keratin 8
Keratin, type I cytoskeletal 8 also known as cytokeratin-8 or keratin-8 is a keratin protein that in human is encoded by the KRT8 gene. It is often paired with keratin 18.-Utility as an immunohistochemical stain:...
and the KRT18
Keratin 18
Keratin 18 is a type I cytokeratin. It is, together with its filament partner keratin 8, perhaps the most commonly found products of the intermediate filament gene family. They are expressed in single layer epithelial tissues of the body. Mutations in this gene have been linked to cryptogenic...
gene.
Pathophysiology
Cofactor (biochemistry)
A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes, and cofactors can be considered "helper molecules" that assist in biochemical transformations....
for a number of enzymes such as ceruloplasmin, cytochrome c oxidase
Cytochrome c oxidase
The enzyme cytochrome c oxidase or Complex IV is a large transmembrane protein complex found in bacteria and the mitochondrion.It is the last enzyme in the respiratory electron transport chain of mitochondria located in the mitochondrial membrane...
, dopamine β-hydroxylase
Dopamine beta hydroxylase
Dopamine β-hydroxylase is an enzyme that converts dopamine to norepinephrine.DBH is a 290 kDa copper-containing oxygenase consisting of four identical subunits, and its activity requires ascorbate as a cofactor...
, superoxide dismutase
Superoxide dismutase
Superoxide dismutases are a class of enzymes that catalyze the dismutation of superoxide into oxygen and hydrogen peroxide. As such, they are an important antioxidant defense in nearly all cells exposed to oxygen...
and tyrosinase
Tyrosinase
Tyrosinase also known as monophenol monooxygenase is an enzyme that catalyses the oxidation of phenols and is widespread in plants and animals...
.
Copper enters the body through the digestive tract
Gastrointestinal tract
The human gastrointestinal tract refers to the stomach and intestine, and sometimes to all the structures from the mouth to the anus. ....
. A transporter protein on the cells of the small bowel
Enterocyte
Enterocytes, or intestinal absorptive cells, are simple columnar epithelial cells found in the small intestines and colon. A glycocalyx surface coat contains digestive enzymes. Microvilli on the apical surface increase surface area for the digestion and transport of molecules from the intestinal...
, copper membrane transporter 1
SLC31A1
High affinity copper uptake protein 1 is a protein that in humans is encoded by the SLC31A1 gene.-Further reading:...
(CMT1), carries copper inside the cells, where some is bound to metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
and part is carried by ATOX1
ATOX1
Copper transport protein ATOX1 is a protein that in humans is encoded by the ATOX1 gene.-Interactions:ATOX1 has been shown to interact with Wilson disease protein and ATP7A.-Further reading:...
to an organelle known as the trans-Golgi network
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
. Here, in response to rising concentrations of copper, an enzyme called ATP7A
ATP7A
Copper-transporting ATPase 1 also known as copper pump 1 or Menkes disease-associated protein is a protein that in humans is encoded by the ATP7A gene.- Gene :...
releases copper into the portal vein to the liver. Liver cells also carry the CMT1 protein, and metallothionein and ATOX1 bind it inside the cell, but here it is ATP7B that links copper to ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
and releases it into the bloodstream, as well as removing excess copper by secreting it into bile
Bile
Bile or gall is a bitter-tasting, dark green to yellowish brown fluid, produced by the liver of most vertebrates, that aids the process of digestion of lipids in the small intestine. In many species, bile is stored in the gallbladder and upon eating is discharged into the duodenum...
. Both functions of ATP7B are impaired in Wilson's disease. Copper accumulates in the liver tissue; ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and rapidly degraded in the bloodstream.
When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage through a process known as Fenton chemistry
Fenton's reagent
Fenton's reagent is a solution of hydrogen peroxide and an iron catalyst that is used to oxidize contaminants or waste waters. Fenton's reagent can be used to destroy organic compounds such as trichloroethylene and tetrachloroethylene ....
; this damage eventually leads to chronic active hepatitis
Hepatitis
Hepatitis is a medical condition defined by the inflammation of the liver and characterized by the presence of inflammatory cells in the tissue of the organ. The name is from the Greek hepar , the root being hepat- , meaning liver, and suffix -itis, meaning "inflammation"...
, fibrosis
Fibrosis
Fibrosis is the formation of excess fibrous connective tissue in an organ or tissue in a reparative or reactive process. This is as opposed to formation of fibrous tissue as a normal constituent of an organ or tissue...
(deposition of connective tissue) and cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
. The liver also releases copper into the bloodstream that is not bound to ceruloplasmin. This free copper precipitates throughout the body but particularly in the kidneys, eyes and brain. In the brain, most copper is deposited in the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
, particularly in the putamen
Putamen
The putamen is a round structure located at the base of the forebrain . The putamen and caudate nucleus together form the dorsal striatum. It is also one of the structures that comprises the basal ganglia. Through various pathways, the putamen is connected to the substantia nigra and globus pallidus...
and globus pallidus
Globus pallidus
The globus pallidus also known as paleostriatum, is a sub-cortical structure of the brain. Topographically, it is part of the telencephalon, but retains close functional ties with the subthalamus - both of which are part of the extrapyramidal motor system...
(together called the lenticular nucleus); these areas normally participate in the coordination of movement as well as playing a significant role in neurocognitive processes such as the processing of stimuli and mood regulation. Damage to these areas, again by Fenton chemistry, produces the neuropsychiatric symptoms seen in Wilson's disease.
It is not clear why Wilson's disease causes hemolysis, but various lines of evidence suggest that high levels of free (non-ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
bound) copper have a direct effect on either oxidation of hemoglobin
Hemoglobin
Hemoglobin is the iron-containing oxygen-transport metalloprotein in the red blood cells of all vertebrates, with the exception of the fish family Channichthyidae, as well as the tissues of some invertebrates...
, inhibition of energy-supplying enzymes in the red blood cell
Red blood cell
Red blood cells are the most common type of blood cell and the vertebrate organism's principal means of delivering oxygen to the body tissues via the blood flow through the circulatory system...
, or direct damage to the cell membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
.
Diagnosis
Liver function tests
Liver function tests , are groups of clinical biochemistry laboratory blood assays designed to give information about the state of a patient's liver. The parameters measured include PT/INR, aPTT, albumin, billirubin and others...
such as a raised aspartate transaminase
Aspartate transaminase
Aspartate transaminase , also called aspartate aminotransferase or serum glutamic oxaloacetic transaminase , is a pyridoxal phosphate -dependent transaminase enzyme . AST catalyzes the reversible transfer of an α-amino group between aspartate and glutamate and, as such, is an important enzyme in...
, alanine transaminase
Alanine transaminase
Alanine transaminase or ALT is a transaminase enzyme . It is also called serum glutamic pyruvic transaminase or alanine aminotransferase ....
and bilirubin
Bilirubin
Bilirubin is the yellow breakdown product of normal heme catabolism. Heme is found in hemoglobin, a principal component of red blood cells. Bilirubin is excreted in bile and urine, and elevated levels may indicate certain diseases...
level. If the liver damage is significant, albumin
Albumin
Albumin refers generally to any protein that is water soluble, which is moderately soluble in concentrated salt solutions, and experiences heat denaturation. They are commonly found in blood plasma, and are unique to other blood proteins in that they are not glycosylated...
may be decreased due to an inability of damaged liver cells to produce this protein; likewise, the prothrombin time
Prothrombin time
The prothrombin time and its derived measures of prothrombin ratio and international normalized ratio are measures of the extrinsic pathway of coagulation. This test is also called "ProTime INR" and "INR PT". They are used to determine the clotting tendency of blood, in the measure of warfarin...
(a test of coagulation
Coagulation
Coagulation is a complex process by which blood forms clots. It is an important part of hemostasis, the cessation of blood loss from a damaged vessel, wherein a damaged blood vessel wall is covered by a platelet and fibrin-containing clot to stop bleeding and begin repair of the damaged vessel...
) may be prolonged as the liver is unable to produce proteins known as clotting factors. Alkaline phosphatase
Alkaline phosphatase
Alkaline phosphatase is a hydrolase enzyme responsible for removing phosphate groups from many types of molecules, including nucleotides, proteins, and alkaloids. The process of removing the phosphate group is called dephosphorylation...
levels are relatively low in those with Wilson's-related acute liver failure. If there are neurological symptoms, magnetic resonance imaging
Magnetic resonance imaging
Magnetic resonance imaging , nuclear magnetic resonance imaging , or magnetic resonance tomography is a medical imaging technique used in radiology to visualize detailed internal structures...
(MRI) of the brain is usually performed; this shows hyperintensities
Hyperintensity
Hyperintensities refer to areas of high intensity on particular types of magnetic resonance imaging scans of the human brain. These small regions of high intensity are observed on T2 weighted MRI images within cerebral white matter or subcortical gray matter Hyperintensities refer to areas of...
in the part of the brain called the basal ganglia
Basal ganglia
The basal ganglia are a group of nuclei of varied origin in the brains of vertebrates that act as a cohesive functional unit. They are situated at the base of the forebrain and are strongly connected with the cerebral cortex, thalamus and other brain areas...
in the T2
Spin-spin relaxation time
thumb|right|T2 relaxation curveSpin–spin relaxation is the mechanism by which Mxy, the transverse component of the magnetization vector, exponentially decays towards its equilibrium value of zero, in nuclear magnetic resonance and magnetic resonance imaging...
setting. MRI may also demonstrate the characteristic "face of the giant panda" pattern.
There is no totally reliable test for Wilson's disease, but levels of ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
and copper in the blood, as well of the amount of copper excreted in urine during a 24-hour period, are together used to form an impression of the amount of copper in the body. The gold standard
Gold standard (test)
In medicine and statistics, gold standard test refers to a diagnostic test or benchmark that is the best available under reasonable conditions. It does not have to be necessarily the best possible test for the condition in absolute terms...
or most ideal test is a liver biopsy
Liver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
.
Ceruloplasmin
Ceruloplasmin
Ceruloplasmin is a ferroxidase enzyme that in humans is encoded by the CP gene.Ceruloplasmin is the major copper-carrying protein in the blood, and in addition plays a role in iron metabolism. It was first described in 1948...
are abnormally low (<0.2 g/L) in 80–95% of cases. It can, however, be present at normal levels in people with ongoing inflammation
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
as it is an acute phase protein
Acute phase protein
Acute-phase proteins are a class of proteins whose plasma concentrations increase or decrease in response to inflammation...
. Low ceruloplasmin is also found in Menkes disease
Menkes disease
Menkes disease , also called Menkes syndrome, copper transport disease, steely hair disease, kinky hair disease, or Menkes kinky hair syndrome, is a disorder that affects copper levels in the body, leading to copper deficiency...
and aceruloplasminemia
Aceruloplasminemia
Aceruloplasminemia is an autosomal recessive disorder of iron metabolism characterized by progressive neurodegeneration of the retina and basal ganglia and diabetes mellitus....
, which are related to, but much rarer than Wilson's disease.
The combination of neurological symptoms, Kayser–Fleisher rings and a low ceruloplasmin level is considered sufficient for the diagnosis of Wilson's disease. In many cases, however, further tests are needed.
Serum and urine copper
Serum copper is paradoxically low but urine copper is elevated in Wilson's disease. Urine is collected for 24 hours in a bottle with a copper-free liner. Levels above 100 μg/24h (1.6 μmol/24h) confirm Wilson's disease, and levels above 40 μg/24h (0.6 μmol/24h) are strongly indicative. High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitisAutoimmune hepatitis
Autoimmune Hepatitis is a disease of the liver that occurs when the body's immune system attacks cells of the liver. Anomalous presentation of human leukocyte antigen class II on the surface of hepatocytes, possibly due to genetic predisposition or acute liver infection, causes a cell-mediated...
and in cholestasis
Cholestasis
In medicine, cholestasis is a condition where bile cannot flow from the liver to the duodenum. The two basic distinctions are an obstructive type of cholestasis where there is a mechanical blockage in the duct system such as can occur from a gallstone or malignancy and metabolic types of...
(any disease obstructing the flow of bile from the liver to the small bowel).
In children, the penicillamine
Penicillamine
Penicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...
test may be used. A 500 mg oral dose of penicillamine is administered, and urine collected for 24 hours. If this contains more than 1600 μg (25 μmol), it is a reliable indicator of Wilson's disease. This test has not been validated in adults.
Liver biopsy
Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsyLiver biopsy
Liver biopsy is the biopsy from the liver. It is a medical test that is done to aid diagnosis of liver disease, to assess the severity of known liver disease, and to monitor the progress of treatment.-History:...
. This is assessed microscopically for the degree of steatosis
Steatosis
In cellular pathology, steatosis is the process describing the abnormal retention of lipids within a cell. It reflects an impairment of the normal processes of synthesis and elimination of triglyceride fat. Excess lipid accumulates in vesicles that displace the cytoplasm...
and cirrhosis
Cirrhosis
Cirrhosis is a consequence of chronic liver disease characterized by replacement of liver tissue by fibrosis, scar tissue and regenerative nodules , leading to loss of liver function...
, and histochemistry and quantification of copper are used to measure the severity of the copper accumulation. A level of 250 μg
Microgram
In the metric system, a microgram is a unit of mass equal to one millionth of a gram , or 1/1000 of a milligram. It is one of the smallest units of mass commonly used...
of copper per gram of dried liver tissue confirms Wilson's disease. Occasionally, lower levels of copper are found; in that case, the combination of the biopsy findings with all other tests could still lead to a formal diagnosis of Wilson's.
In the earlier stages of the disease, the biopsy typically shows steatosis
Fatty liver
Fatty liver, also known as fatty liver disease , is a reversible condition where large vacuoles of triglyceride fat accumulate in liver cells via the process of steatosis...
(deposition of fatty material), increased glycogen
Glycogen
Glycogen is a molecule that serves as the secondary long-term energy storage in animal and fungal cells, with the primary energy stores being held in adipose tissue...
in the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
, and areas of necrosis
Necrosis
Necrosis is the premature death of cells in living tissue. Necrosis is caused by factors external to the cell or tissue, such as infection, toxins, or trauma. This is in contrast to apoptosis, which is a naturally occurring cause of cellular death...
(cell death). In more advanced disease, the changes observed are quite similar to those seen in autoimmune hepatitis, such as infiltration by inflammatory
Inflammation
Inflammation is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. Inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process...
cells, piecemeal necrosis and fibrosis (scar tissue). In advanced disease, finally, cirrhosis is the main finding. In acute liver failure, degeneration of the liver cells and collapse of the liver tissue architecture is seen, typically on a background of cirrhotic changes. Histochemical methods for detecting copper are inconsistent and unreliable, and taken alone are regarded as insufficient to establish a diagnosis.
Genetic testing
Mutation analysis of the ATP7B gene, as well as other genes linked to copper accumulation in the liver, may be performed. Once a mutation is confirmed, it is possible to screen family members for the disease as part of clinical genetics family counselling.Dietary
In general, a diet low in copper-containing foods is recommended, with the avoidance of mushroomMushroom
A mushroom is the fleshy, spore-bearing fruiting body of a fungus, typically produced above ground on soil or on its food source. The standard for the name "mushroom" is the cultivated white button mushroom, Agaricus bisporus; hence the word "mushroom" is most often applied to those fungi that...
s, nuts
Nut (fruit)
A nut is a hard-shelled fruit of some plants having an indehiscent seed. While a wide variety of dried seeds and fruits are called nuts in English, only a certain number of them are considered by biologists to be true nuts...
, chocolate
Chocolate
Chocolate is a raw or processed food produced from the seed of the tropical Theobroma cacao tree. Cacao has been cultivated for at least three millennia in Mexico, Central and South America. Its earliest documented use is around 1100 BC...
, dried fruit
Fruit
In broad terms, a fruit is a structure of a plant that contains its seeds.The term has different meanings dependent on context. In non-technical usage, such as food preparation, fruit normally means the fleshy seed-associated structures of certain plants that are sweet and edible in the raw state,...
, liver, and shellfish
Shellfish
Shellfish is a culinary and fisheries term for exoskeleton-bearing aquatic invertebrates used as food, including various species of molluscs, crustaceans, and echinoderms. Although most kinds of shellfish are harvested from saltwater environments, some kinds are found only in freshwater...
.
Medication
Various treatments are available for Wilson's disease. Some increase the removal of copper from the body, while others prevent the absorption of copper from the diet.Generally, penicillamine
Penicillamine
Penicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...
is the first treatment used. This binds copper (chelation
Chelation
Chelation is the formation or presence of two or more separate coordinate bonds between apolydentate ligand and a single central atom....
) and leads to excretion of copper in the urine. Hence, monitoring of the amount of copper in the urine can be done to ensure a sufficiently high dose is taken. Penicillamine is not without problems: about 20% experience a side effect or complication of penicillamine treatment, such as drug-induced lupus
Systemic lupus erythematosus
Systemic lupus erythematosus , often abbreviated to SLE or lupus, is a systemic autoimmune disease that can affect any part of the body. As occurs in other autoimmune diseases, the immune system attacks the body's cells and tissue, resulting in inflammation and tissue damage...
(causing joint pains and a skin rash) or myasthenia
Myasthenia gravis
Myasthenia gravis is an autoimmune neuromuscular disease leading to fluctuating muscle weakness and fatiguability...
(a nerve condition leading to muscle weakness). In those who presented with neurological symptoms, almost half experience a paradoxical worsening in their symptoms. While this phenomenon is also observed in other treatments for Wilson's, it is usually taken as an indication for discontinuing penicillamine and commencing second-line treatment. Intolerant to penicillamine may instead be commenced on trientine hydrochloride, which also has chelating properties. Some recommend trientine as first-line treatment, but experience with penicillamine is more extensive. A further agent with known activity in Wilson's disease is tetrathiomolybdate. This is still regarded as experimental, although some studies have shown a beneficial effect.
Once all results have returned to normal, zinc
Zinc
Zinc , or spelter , is a metallic chemical element; it has the symbol Zn and atomic number 30. It is the first element in group 12 of the periodic table. Zinc is, in some respects, chemically similar to magnesium, because its ion is of similar size and its only common oxidation state is +2...
(usually in the form of a zinc acetate
Zinc acetate
Zinc acetate is the chemical compound with the formula Zn2, which commonly occurs as a dihydrate Zn22. Both the hydrate and the anhydrous forms are colorless solids that are commonly used in chemical synthesis and as dietary supplements. Zinc acetates are prepared by the action of acetic acid on...
prescription called Galzin) may be used instead of chelators to maintain stable copper levels in the body. Zinc stimulates metallothionein
Metallothionein
Metallothionein is a family of cysteine-rich, low molecular weight proteins. They are localized to the membrane of the Golgi apparatus...
, a protein in gut cells that binds copper and prevents their absorption and transport to the liver. Zinc therapy is continued unless symptoms recur, or if the urinary excretion of copper increases.
In rare cases where none of the oral treatments are effective, especially in severe neurological disease, dimercaprol
Dimercaprol
Dimercaprol or British anti-Lewisite , is a compound developed by British biochemists at Oxford University during World War II. It was developed secretly as an antidote for lewisite, the now-obsolete arsenic-based chemical warfare agent. Today, it is used medically in treatment of arsenic,...
(British anti-Lewisite) is still occasionally necessary. This treatment is injected intramuscularly
Intramuscular injection
Intramuscular injection is the injection of a substance directly into a muscle. In medicine, it is one of several alternative methods for the administration of medications . It is used for particular forms of medication that are administered in small amounts...
(into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.
People who are asymptomatic
Asymptomatic
In medicine, a disease is considered asymptomatic if a patient is a carrier for a disease or infection but experiences no symptoms. A condition might be asymptomatic if it fails to show the noticeable symptoms with which it is usually associated. Asymptomatic infections are also called subclinical...
(for instance those diagnosed through family screening or only as a result of abnormal test results) are generally treated, as the copper accumulation may cause long-term damage in the future. It is unclear whether these people are best treated with penicillamine or zinc acetate.
Physical therapy
Physiotherapy is beneficial for those patients with the neurologic form of the disease. The copper chelating treatment may take up to six months to start working, and physical therapy can assist in coping with ataxiaAtaxia
Ataxia is a neurological sign and symptom that consists of gross lack of coordination of muscle movements. Ataxia is a non-specific clinical manifestation implying dysfunction of the parts of the nervous system that coordinate movement, such as the cerebellum...
, dystonia
Dystonia
Dystonia is a neurological movement disorder, in which sustained muscle contractions cause twisting and repetitive movements or abnormal postures. The disorder may be hereditary or caused by other factors such as birth-related or other physical trauma, infection, poisoning or reaction to...
, and tremors, as well as preventing the development of contracture
Contracture
A muscle contracture is a permanent shortening of a muscle or joint.. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spastic cerebral palsy....
s that can result from dystonia.
Transplantation
Liver transplantationLiver transplantation
Liver transplantation or hepatic transplantation is the replacement of a diseased liver with a healthy liver allograft. The most commonly used technique is orthotopic transplantation, in which the native liver is removed and replaced by the donor organ in the same anatomic location as the original...
is an effective cure for Wilson's disease, but is used only in particular scenarios because of the numerous risks and complications associated with the procedure. It is used mainly in people with fulminant liver failure who fail to respond to medical treatment, or in those with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.
History
The disease bears the name of the BritishUnited Kingdom
The United Kingdom of Great Britain and Northern IrelandIn the United Kingdom and Dependencies, other languages have been officially recognised as legitimate autochthonous languages under the European Charter for Regional or Minority Languages...
physician Samuel Alexander Kinnier Wilson
Samuel Alexander Kinnier Wilson
Samuel Alexander Kinnier Wilson was a British neurologist who was the first to describe Wilson's disease.-Biography:...
(1878–1937), a neurologist
Neurology
Neurology is a medical specialty dealing with disorders of the nervous system. Specifically, it deals with the diagnosis and treatment of all categories of disease involving the central, peripheral, and autonomic nervous systems, including their coverings, blood vessels, and all effector tissue,...
who described the condition, including the pathological changes in the brain and liver, in 1912. Wilson's work had been predated by, and drew on, reports from German neurologist Carl Westphal
Carl Friedrich Otto Westphal
Carl Friedrich Otto Westphal was a German neurologist and psychiatrist from Berlin. He was the son of Otto Carl Friedrich Westphal and Karoline Friederike Heine and the father of Alexander Carl Otto Westphal...
(in 1883), who termed it "pseudosclerosis"; by the British neurologist William Gowers
William Richard Gowers
Sir William Richard Gowers was a British neurologist.The Gowers' tract is named after him....
(in 1888); and by Adolph Strümpell
Adolph Strümpell
Ernst Adolf Gustav Gottfried von Strümpell was a German neurologist who was born at Neu-Autz Estate, Courland Governorate...
(in 1898), who noted hepatic cirrhosis. Neuropathologist John Nathaniel Cumings made the link with copper accumulation in both the liver and the brain in 1948. The occurrence of hemolysis was noted in 1967.
Cumings, and simultaneously the New Zealand neurologist Derek Denny-Brown
Derek Denny-Brown (doctor)
Derek Ernest Denny-Brown OBE was a neurologist. Working in Oxford, London and Boston, he made major contributions to the field of neurology, such as the development of electromyography, physiology of micturition and the treatment of Wilson's disease.-Biography:Born in New Zealand, he studied at...
, working in the United States, first reported effective treatment with metal chelator British anti-Lewisite
Dimercaprol
Dimercaprol or British anti-Lewisite , is a compound developed by British biochemists at Oxford University during World War II. It was developed secretly as an antidote for lewisite, the now-obsolete arsenic-based chemical warfare agent. Today, it is used medically in treatment of arsenic,...
in 1951. This treatment had to be injected but was one of the first therapies available in the field of neurology, a field that classically was able to observe and diagnose but had few treatments to offer. The first effective oral chelation agent, penicillamine
Penicillamine
Penicillamine is a pharmaceutical of the chelator class. It is sold under the trade names of Cuprimine and Depen. The pharmaceutical form is D-penicillamine, as L-penicillamine is toxic...
, was discovered in 1956 by British neurologist John Walshe. In 1982, Walshe also introduced trientine, and was the first to develop tetrathiomolybdate for clinical use. Zinc acetate therapy initially made its appearance in the Netherlands, where physicians Schouwink and Hoogenraad used it in 1961 and in the 1970s, respectively, but it was further developed later by Brewer and colleagues at the University of Michigan
University of Michigan
The University of Michigan is a public research university located in Ann Arbor, Michigan in the United States. It is the state's oldest university and the flagship campus of the University of Michigan...
.
The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and 1990s by several research groups.
In other animals
Hereditary copper accumulation has been described in Bedlington TerrierBedlington Terrier
The Bedlington Terrier is a breed of terrier named after the mining town of Bedlington, Northumberland in North East England.- Description :Appearance:...
s, where it generally only affects the liver. It is due to mutations in the COMMD1
COMMD1
COMM domain-containing protein 1 is a protein that in humans is encoded by the COMMD1 gene. It was originally regarded as Murr1 before being differentiated and renamed by Dr. Ezra Burstein's Lab-Further reading:...
(or MURR1) gene. In non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis), no COMMD1 mutations could be detected to explain their genetic origin.
External links
- Wilson's disease association international
- Wilson's disease UK
- Children's Liver Disease Foundation (UK)
- Wilson Disease Mutation Database (HUGOHuman Genome OrganisationThe Human Genome Organisation is an organization involved in the Human Genome Project, a project about mapping the human genome. HUGO was established in 1989 as an international organization, primarily to foster collaboration between genome scientists around the world...
)