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(New page: {{ClinPsy}} {{Infobox_Disease | Name = Wilson's disease | Image = | Caption = | DiseasesDB = 14152 | ICD10 = {{ICD10|E|83|0|e|70}} | ICD9...)
 
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{{Infobox disease |
Name = Wilson's disease |
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Name = Wilson disease |
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Image = PBB Protein ATP7B image.jpg |
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Caption = Mutations in the ''[[ATP7B]]'' gene are present in the majority of patients with Wilson's disease. |
 
DiseasesDB = 14152 |
 
DiseasesDB = 14152 |
 
ICD10 = {{ICD10|E|83|0|e|70}} |
 
ICD10 = {{ICD10|E|83|0|e|70}} |
 
ICD9 = {{ICD9|275.1}} |
 
ICD9 = {{ICD9|275.1}} |
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OMIM = 277900 |
 
OMIM = 277900 |
 
MedlinePlus = 000785 |
 
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eMedicine_mult = {{eMedicine2|neuro|570}} {{eMedicine2|ped|2441}} |
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'''Wilson's disease''' or '''hepatolenticular degeneration''' is an [[autosomal recessive]] [[hereditary disease]], with an incidence of about 1 in 30,000 in most parts of the world and a male preponderance. Its main feature is accumulation of [[copper]] in [[biological tissue|tissues]], which manifests itself with [[neurology|neurological]] symptoms and [[liver]] disease. The estimated [[heterozygous]] [[Asymptomatic carrier|carrier]] rate is about 1 in 100, meaning that 1 in 100 people are unaffected carriers of this [[mutation]].
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'''Wilson's disease''' or '''hepatolenticular degeneration''' is an [[autosomal recessive]] [[genetic disorder]] in which [[copper]] accumulates in [[biological tissue|tissues]]; this manifests as [[neurology|neurological]] or [[psychiatry|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 transplantation|liver transplant]] is required.<ref name=Ala/>
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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 [[Genetic carrier|carrier]]s). If a child inherits the gene from both parents, they may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older patients have been described. Wilson's disease occurs in 1 to 4 per 100,000 people.<ref name=Ala/> Wilson's disease is named after [[Samuel Alexander Kinnier Wilson|Dr. Samuel Alexander Kinnier Wilson]] (1878-1937), the British neurologist who first described the condition in 1912.<ref name=Wilson1912/>
   
 
==Signs and symptoms==
 
==Signs and symptoms==
[[Image:autorecessive.svg|thumb|right|Wilson disease is inherited in an autosomal recessive fashion.]]
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The main sites of copper accumulation are the [[liver]] and the [[brain]], and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.<ref name=Ala>{{cite journal |author=Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML |title=Wilson's disease |journal=Lancet |volume=369 |issue=9559 |pages=397–408 |year=2007 |pmid=17276780 |doi=10.1016/S0140-6736(07)60196-2}}</ref> Patients 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 patients, when tested, turn out to have been experiencing symptoms of the condition but haven't received a diagnosis.<ref name=Merle2007>{{cite journal |author=Merle U, Schaefer M, Ferenci P, Stremmel W |title=Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study |journal=Gut |volume=56 |issue=1 |pages=115–20 |year=2007 |pmid=16709660 |doi=10.1136/gut.2005.087262 | url=http://gut.bmj.com/cgi/content/full/56/1/115}}</ref>
Symptoms usually appear around the ages of 10 to 21 years, but sometimes not until the age of 30, and in rare instances at age 50 and even beyond. Presentation before 5 years of age is extremely rare, despite the biochemical defect being present at birth.
 
   
The age of presentation seems to correlate with the organ system involved. About half (40&ndash;50%) of patients first present with hepatic symptoms and half (40&ndash;50%) with neurologic symptoms. The average age for hepatic symptoms is 10&ndash;14 years, compared with 19&ndash;22 years for neurologic symptoms. Patients rarely present after age 40.
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===Liver disease===
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Liver disease may present as [[tiredness]], increased bleeding tendency or confusion (due to [[hepatic encephalopathy]]) 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, [[splenomegaly]] (enlargement of the spleen) and [[ascites]] (accumulation of fluid in the abdominal cavity). On examination, signs of chronic liver disease such as [[spider angioma|spider naevi]] (small distended blood vessels, usually on the chest) may be observed. [[Chronic active hepatitis]] has caused [[cirrhosis]] of the liver in most patients 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.<ref name=Ala/>
   
The main features are liver and neuropsychiatric problems. [[Chronic active hepatitis]], culminating in [[cirrhosis]] is the most common hepatic presentation, but some patients present with [[fulminant]] [[liver failure]] (which is characterised by remarkably low [[alkaline phosphatase]] and often high [[bilirubin]] levels compared to similar disease states<ref>Shaver WA, Bhatt H, Combes B. Low serum alkaline phosphatase activity in Wilson's disease. ''Hepatology'' 1986;6:859-63. PMID 3758940.</ref>) and a surprisingly rare incidence of [[hepatocellular carcinoma]]. Neuropsychiatric phenomena are early [[dementia]], [[mood disorder]]s or [[psychosis]] and signs of [[asterixis]] (a flapping [[tremor]] of the hands) and [[parkinsonism]] (including [[ataxia]], [[dyskinesia]], and [[rigidity]]).
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About 5% of all patients 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 patient develops [[hepatic encephalopathy]] (confusion, coma, seizures and finally life-threatening [[Cerebral edema|swelling of the brain]]).<ref name=Ala/>
   
Adjunctive features are [[kidney|renal]] ([[renal tubular acidosis]], [[nephrolithiasis|kidney stones]]), [[eye|ophthalmic]] ([[Kayser-Fleischer ring]]s, sunflower [[cataract]]s), [[heart|cardiac]] ([[cardiomyopathy]], [[cardiac arrhythmia]]s) and [[skin|dermal]] ([[hidradenitis suppurativa]]). [[Hemolysis]] (anemia due to destruction of red blood cells) is usually present only in severe cases.
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===Neuropsychiatric symptoms===
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About half the patients with Wilson's have neurological or psychiatric problems. Most patients initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms then follow, often in the form of [[parkinsonism]] (increased rigidity and slowing of routine movements) 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.<ref name=Ala/>
   
== Diagnosis ==
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Psychiatric problems due to Wilson's disease may include behavioral changes, [[clinical depression|depression]], [[anxiety]] and [[psychosis]].<ref name=Ala/>
A suppressed level of [[ceruloplasmin]] is present in over 80% of patients, and this is commonly performed as a screening test in patients with liver problems. A more accurate measurement is the direct testing for copper levels in a 24h specimen of urine, in the [[blood]] or in the sample obtained by [[liver biopsy]]. The average concentration of hepatic copper may reach 20 times normal levels, whilst plasma [[ceruloplasmin]] levels are typically less than 30% of normal.
 
   
An eye exam would detect the [[Kayser-Fleischer ring]], although its absence does not rule out Wilson's and it may be missed on cursory examination. This sign is characterised by brown rings around the cornea in the eye that result from copper deposition in [[Descemet's membrane]] of the [[cornea]]. Wilson's disease is also associated with sunflower cataracts, brown or green pigmentation of the anterior and posterior lens capsule.
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===Other organ systems===
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[[Image:Kayser-Fleischer ring.jpg|thumb|A Kayser-Fleischer ring in a patient with symptoms suggestive of Wilson's disease]]
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Various medical conditions have been linked with copper accumulation in Wilson's disease:
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* Eyes: ''[[Kayser-Fleischer ring]]s'' (KF rings) may be visible around the iris. They are due to copper deposition in [[Descemet's membrane]] of the [[cornea]]. They do not occur in all patients and may only be visible on [[slit lamp]] examination. Wilson's disease is also associated with sunflower [[cataract]]s, brown or green pigmentation of the anterior and posterior lens capsule. Neither cause significant visual loss.<ref name=Ala/> KF rings occur in 66% of cases, more often in those with neurological than with liver problems.<ref name=Merle2007/>
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* Kidneys: [[renal tubular acidosis#Type 2-Proximal RTA|renal tubular acidosis]], a disorder of [[bicarbonate]] handling by the [[proximal tubule]]s leads to [[nephrocalcinosis]] (calcium accumulation in the kidneys), weakening of the bone (due to calcium and phosphate loss) and occasionally [[aminoaciduria]] (loss of [[amino acid]]s, needed for protein synthesis).<ref name=Ala/>
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* Heart: [[cardiomyopathy]] (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 arrhythmia]]s (episodes of irregular and/or abnormally fast or slow heart beat).<ref name=Ala/>
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* Hormones: [[hypoparathyroidism]] (failure of the [[parathyroid gland]]s, leading to low calcium levels), [[infertility]] and [[habitual abortion]].<ref name=Ala/>
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==Diagnosis==
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[[Image:Brain structure.gif|thumb|Location of the basal ganglia, the part of the brain affected by Wilson's disease]]
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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 patients 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.<ref name=Ala/> [[Alkaline phosphatase]] levels are relatively low in patients with Wilson's-related acute liver failure.<ref name="pmid3758940">{{cite journal |author=Shaver WA, Bhatt H, Combes B |title=Low serum alkaline phosphatase activity in Wilson's disease |journal=Hepatology |volume=6 |issue=5 |pages=859–63 |year=1986 |pmid=3758940 |doi=10.1002/hep.1840060509}}</ref> If there are neurological symptoms, [[magnetic resonance imaging]] (MRI) of the brain is usually performed; this shows [[hyperintensity|hyperintensities]] in the part of the brain called the [[basal ganglia]] in the [[spin-spin relaxation time|T2]] setting.<ref name=Roberts>{{cite journal| author=Roberts EA, Schilsky ML |title=A practice guideline on Wilson disease |journal=Hepatology |year=2003 |volume=37 |issue=6 |pages=1475–92 |pmid=12774027 |doi=10.1053/jhep.2003.50252 |url=http://www3.interscience.wiley.com/cgi-bin/fulltext/106595824/PDFSTART |format=PDF}}</ref> MRI may also demonstrate the characteristic "face of the giant panda" pattern.<ref name=Panda>{{cite journal |author=Das SK, Ray K |title=Wilson's disease: an update |journal=Nat Clin Pract Neurol |volume=2 |issue=9 |pages=482–93 |year=2006 |month=September |pmid=16932613 |doi=10.1038/ncpneuro0291 | url=http://www.nature.com/nrneurol/journal/v2/n9/full/ncpneuro0291.html}}</ref>
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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 (test)|gold standard]] or most ideal test is a [[liver biopsy]].<ref name=Ala/>
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===Ceruloplasmin===
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[[Image:PBB Protein CP image.jpg|thumb|Ceruloplasmin]]
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Levels of [[ceruloplasmin]] are abnormally low (<0.2&nbsp;gram/liter) in 80-95% of cases.<ref name=Ala/> 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.<ref name=Ala/><ref name=Roberts/>
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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.<ref name=Roberts/>
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===Serum and urine copper===
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Serum copper is paradoxically low but urine copper are elevated in Wilson's disease. Urine is collected for 24 hours in a bottle with a copper-free liner. Levels above 100&nbsp;μg/24h (1.6&nbsp;μmol/24h) confirm Wilson's disease, and levels above 40&nbsp;μg/24h (0.6&nbsp;μmol/24h) are strongly indicative.<ref name=Ala/> High urine copper levels are not unique to Wilson's disease; they are sometimes observed in [[autoimmune hepatitis]] and in [[cholestasis]] (any disease obstructing the flow of bile from the liver to the small bowel).<ref name=Roberts/>
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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&nbsp;μg (25&nbsp;μmol), it is a reliable indicator of Wilson's disease. This test has not been validated in adults.<ref name=Roberts/>
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===Liver biopsy===
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Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a [[liver biopsy]]. 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&nbsp;[[microgram|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.<ref name=Ala/>
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In the earlier stages of the disease, the biopsy typically shows [[fatty liver|steatosis]] (deposition of fatty material), increased [[glycogen]] in the [[Cell nucleus|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 [[inflammation|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.<ref name=Roberts/>
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===Genetic testing===
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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.<ref name=Ala/>
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==Genetics==
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[[Image:autorecessive.svg|thumb|Wilson's disease has an autosomal recessive pattern of inheritance.]]
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{{main|ATP7B}}
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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-ATPase|P-type]] (cation transport enzyme) [[ATPase]] that transports copper into [[bile]] and incorporates it into [[ceruloplasmin]].<ref name=Ala/> Mutations can be detected in 90% of patients. Most (60%) are [[homozygous]] for ''ATP7B'' mutations (two abnormal copies), and 30% have only one abnormal copy. 10% have no detectable mutation.<ref name=Merle2007/>
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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.<ref name=Ala/><ref name=deBie2007>{{cite journal |author=de Bie P, Muller P, Wijmenga C, Klomp LW |title=Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes |journal=J. Med. Genet. |volume=44 |issue=11 |pages=673–88 |year=2007 |month=November |pmid=17717039 |doi=10.1136/jmg.2007.052746 |url=http://jmg.bmj.com/cgi/content/full/44/11/673}}</ref>
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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.<ref>{{cite journal |author=Grubenbecher S, Stüve O, Hefter H, Korth C |title=Prion protein gene codon 129 modulates clinical course of neurological Wilson disease |journal=Neuroreport |volume=17 |issue=5 |pages=549–52 |year=2006 |pmid=16543824 |doi=10.1097/01.wnr.0000209006.48105.90}}</ref> A role for the ''[[Apolipoprotein E|ApoE]]'' gene was initially suspected but could not be confirmed.<ref name=deBie2007/>
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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 patients have no family history of the condition.<ref name=deBie2007/> People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.<ref name=Roberts/>
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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 ''[[Keratin 8|KRT8]]'' and the ''[[Keratin 18|KRT18]]'' gene.<ref name=deBie2007/>
   
 
==Pathophysiology==
 
==Pathophysiology==
The ''Wilson disease gene'' (''[[ATP7B]]'') has been mapped to [[chromosome 13]] (13q14.3) and is expressed primarily in the liver, [[kidney]], and [[placenta]] but has also been found in the [[heart]], [[brain]], and [[lung]], albeit at much lower levels. The gene codes for a P-type [[ATPase]] that transports copper into [[bile]] and incorporates it into [[ceruloplasmin]].
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[[Image:Copper metabolism.png|thumb|Normal absorption and distribution of copper. Cu = copper, CP = [[ceruloplasmin]], green = ATP7B carrying copper.]]
   
The mutant form of ''ATP7B'' expressed in people with Wilson's disease inhibits the release of copper into bile. As the excretion of copper from the body is thus impaired, the copper builds up in the liver and injures liver tissue. Eventually, the damage causes the liver to release the copper directly into the bloodstream, which carries the copper throughout the body. The copper buildup leads to damage in the kidneys, brain, and eyes, presumably by generation of [[reactive oxygen species]] and binding to [[melanin|neuromelanin]][http://www.drproctor.com/crcpap2.htm]. If not treated, Wilson's disease can cause severe brain damage, liver failure, and [[death]].
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Copper is needed by the body for a [[Copper#Biological_role|number of functions]], predominantly as a [[Cofactor (biochemistry)|cofactor]] for a number of enzymes such as ceruloplasmin, [[cytochrome c oxidase]], [[dopamine beta hydroxylase|dopamine β-hydroxylase]], [[superoxide dismutase]] and [[tyrosinase]].<ref name=deBie2007/>
   
Copper deposits in the [[basal ganglia]], particularly in the [[putamen]] and [[globus pallidus]] (together called the ''[[lenticular nucleus]]''), result in cell death, producing symptoms akin to [[Parkinson's disease]].
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Copper enters the body through the [[Gastrointestinal tract|digestive tract]]. A transporter protein on the [[enterocyte|cells of the small bowel]], [[SLC31A1|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 [[Golgi apparatus|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.<ref name=deBie2007/>
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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's reagent|Fenton chemistry]]; this damage eventually leads to [[hepatitis|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.<ref name=deBie2007/>
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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]].<ref>{{cite book |last=Lee |first=GR |editor=Lee GR, Foerster J, Lukens J ''et al.'' |title=Wintrobe's clinical hematology |edition=10th |volume=vol 1 |year=1999 |publisher=Williams & Wilkins |isbn=0-683-18242-0 |pages=1298 |chapter=Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents }}</ref>
   
 
== Treatment ==
 
== Treatment ==
The disease is treated with lifelong use of [[Chelation|chelating agents]] such as D-[[penicillamine]] or [[trientine hydrochloride]], [[medication|drug]]s that help remove copper from [[biological tissue|tissue]]. Patients will also need to take [[vitamin B6]] and follow a low-copper diet, which means avoiding [[mushroom]]s, [[nut (fruit)|nuts]], [[chocolate]], dried [[fruit]], liver, and [[shellfish]].
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===Medical treatment===
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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. In general, a diet low in copper-containing foods ([[mushroom]]s, [[nut (fruit)|nuts]], [[chocolate]], dried [[fruit]], liver, and [[shellfish]]) is recommended.<ref name=Ala/>
   
Taking extra [[zinc]] may be helpful in blocking the [[intestine]]s' absorption of copper. Zinc acetate is an agent utilized to inhibit copper absorption in patients with Wilson's disease. It blocks the intestinal absorption of the metal both from the diet and endogenous secretions. It also acts by producing metallothionein, a protein that binds with copper to prevent its release into the blood, and facilitates elimination via the stool.
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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% of patients experience a side effect or complication of penicillamine treatment, such as drug-induced [[systemic lupus erythematosus|lupus]] (causing joint pains and a skin rash) or [[myasthenia gravis|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.<ref name=Ala/><ref name=Roberts/> Patients 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.<ref name=Roberts/> A further agent with known activity in Wilson's disease is [[tetrathiomolybdate]]. This is still regarded as experimental,<ref name=Roberts/> although some studies have shown a beneficial effect.<ref name=Ala/>
   
[[Liver transplantation]] is effective in patients with fulminant Wilson disease that does not respond to the usual treatment. Because the primary defect resides within the liver, transplantation is curative, but as it is only undertaken in severely ill patients the prognosis is still mediocre.
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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.<ref name=Roberts/>
   
==Epidemiology==
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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 [[Intramuscular injection|intramuscularly]] (into a muscle) every few weeks, and has a number of unpleasant side effects such as pain.<ref name=Walshe1996>{{cite journal |author=Walshe JM |title=Treatment of Wilson's disease: the historical background |journal=QJM |volume=89 |issue=7 |pages=553–5 |year=1996 |month=July |pmid=8759497}}</ref>
In Western populations the incidence is around 1 per 30,000, with a carrier rate of 1 in 100. The gene frequency is much higher in Hispanics, especially in Central America, and in El Salvador, the incidence is 1 in 186. In [[Usulután Department]], El Salvador it has been reported that 1 in 4 persons carry the disease.{{Fact|date=February 2007}}
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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.<ref name=Roberts/>
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===Liver transplantation===
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[[Liver transplantation]] is the only 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 patients with fulminant liver failure who fail to respond to medical treatment, or in patients with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.<ref name=Ala/><ref name=Roberts/>
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==Other species==
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Hereditary copper accumulation has been described in [[Bedlington Terrier]]s,<ref>{{cite journal |author=Sternlieb I, Twedt DC, Johnson GF, ''et al.'' |title=Inherited copper toxicity of the liver in Bedlington terriers |journal=Proc. R. Soc. Med. |volume=70 Suppl 3 |issue= |pages=8–9 |year=1977 |pmid=122681}}</ref> where it generally only affects the liver. It is due to mutations in the ''[[COMMD1]]'' (or ''MURR1'') gene.<ref>{{cite journal |author=van De Sluis B, Rothuizen J, Pearson PL, van Oost BA, Wijmenga C |title=Identification of a new copper metabolism gene by positional cloning in a purebred dog population |journal=Hum. Mol. Genet. |volume=11 |issue=2 |pages=165–73 |year=2002 |pmid=11809725 |url=http://hmg.oxfordjournals.org/cgi/content/full/11/2/165 |doi=10.1093/hmg/11.2.165}}</ref> In patients with non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis), no ''COMMD1'' mutations could be detected to explain their genetic origin.<ref>{{cite journal |author=Müller T, van de Sluis B, Zhernakova A, ''et al.'' |title=The canine copper toxicosis gene MURR1 does not cause non-Wilsonian hepatic copper toxicosis |journal=J. Hepatol. |volume=38 |issue=2 |pages=164–8 |year=2003 |pmid=12547404 |doi=10.1016/S0168-8278(02)00356-2}}</ref>
   
 
==History==
 
==History==
The disease bears the name of the [[United Kingdom|British]] physician Dr [[Samuel Alexander Kinnier Wilson]] (1878-1937), a [[Neurology|neurologist]]<ref>[[Dorland's Medical Dictionary]]</ref> who described the condition in [[1912]].<ref>Wilson SAK. Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. ''Brain'' 1912;34:295-507.</ref> Dr J.N. Cumings made the link with copper accumulation in 1948.<ref>Cumings JN. The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration. ''Brain'' 1948;71:410-5.</ref> The first effective chelation agent, [[penicillamine]], was discovered in 1956 by Dr John Walshe.<ref>Walshe JM. Penicillamine, a new oral therapy for Wilson's disease. ''Am J Med'' 1956;21:487-95. PMID 13362281.</ref> The genetic basis was elucidated in the 1980s and 1990s by several research groups.<ref>Tanzi RE, Petrukhin K, Chernov I, Pellequer JL, Wasco W ''et al'', Ross B, Romano DM, Parano E, Pavone L, Brzustowicz LM, et al. The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene. ''Nat Genet'' 1993;5:344-50. PMID 8298641.</ref><ref>Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. ''Nat Genet'' 1993;5:327-37. PMID 8298639.</ref>
+
The disease bears the name of the [[United Kingdom|British]] physician Dr [[Samuel Alexander Kinnier Wilson]] (1878-1937), a [[Neurology|neurologist]] who described the condition, including the pathological changes in the brain and liver, in 1912.<ref name=Wilson1912>{{cite journal| author=Kinnier Wilson SA | title=Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver | journal=Brain | year=1912 | volume=34 | issue=1 | pages=295–507 | doi=10.1093/brain/34.4.295 | url=http://brain.oxfordjournals.org/cgi/reprint/34/4/295 | format=PDF}}</ref> Wilson's work had been predated by, and drew on, reports from the German neurologist Dr [[Carl Friedrich Otto Westphal|Carl Westphal]] (in 1883), who termed it "pseudosclerosis", by the British neurologist Dr [[William Richard Gowers|William Gowers]] (in 1888), and by Dr [[Adolph Strümpell]] (in 1898), who noted hepatic cirrhosis.<ref name=Robertson>{{cite journal |author=Robertson WM |title=Wilson's disease |journal=Arch. Neurol. |volume=57 |issue=2 |pages=276–7 |year=2000 |month=February |pmid=10681092 |url=http://archneur.ama-assn.org/cgi/content/full/57/2/276 |doi=10.1001/archneur.57.2.276}}</ref> Prof John N. Cumings made the link with copper accumulation in both the liver and the brain in 1948.<ref name="pmid18124738">{{cite journal |author=Cumings JN |title=The copper and iron content of brain and liver in the normal and in hepato-lenticular degeneration |journal=Brain |volume=71 |issue=Dec |pages=410–5 |year=1948 |pmid=18124738 | doi=10.1093/brain/71.4.410 | url=http://brain.oxfordjournals.org/cgi/reprint/71/4/410 |format=PDF}}</ref> The occurrence of hemolysis was noted in 1967.<ref>{{cite journal |author=McIntyre N, Clink HM, Levi AJ, Cumings JN, Sherlock S |title=Hemolytic anemia in Wilson's disease |journal=N. Engl. J. Med. |volume=276 |issue=8 |pages=439–44 |year=1967 |month=February |pmid=6018274}}</ref>
  +
  +
Cumings, and simultaneously the New Zealand neurologist Dr [[Derek Denny-Brown (doctor)|Derek Denny-Brown]], working in the USA, first reported effective treatment with metal chelator [[dimercaprol|British anti-Lewisite]] in 1951.<ref>{{cite journal |author=Cumings JN |title=The effects of B.A.L. in hepatolenticular degeneration |journal=Brain |volume=74 |issue=1 |pages=10–22 |year=1951 |month=March |pmid=14830662 |doi=10.1093/brain/74.1.10}}</ref><ref>{{cite journal |author=Denny-Brown D, Porter H |title=The effect of BAL (2,3-dimercaptopropanol) on hepatolenticular degeneration (Wilson's disease) |journal=N. Engl. J. Med. |volume=245 |issue=24 |pages=917–25 |year=1951 |month=December |pmid=14882450}}</ref> 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 available.<ref name=Robertson/><ref>{{cite journal |author=Vilensky JA, Robertson WM, Gilman S |title=Denny-Brown, Wilson's disease, and BAL (British antilewisite [2,3-dimercaptopropanol]) |journal=Neurology |volume=59 |issue=6 |pages=914–6 |year=2002 |month=September |pmid=12297577}}</ref> The first effective oral chelation agent, [[penicillamine]], was discovered in 1956 by the British neurologist Dr John Walshe.<ref name=Walshe1956>{{cite journal |author=Walshe JM |title=Wilson's disease; new oral therapy |journal=Lancet |volume=267 |issue=6906 |pages=25–6 |year=1956 |month=January |pmid=13279157 |doi=10.1016/S0140-6736(56)91859-1}}</ref> In 1982, Walshe also introduced trientine,<ref>{{cite journal |author=Walshe JM |title=Treatment of Wilson's disease with trientine (triethylene tetramine) dihydrochloride |journal=Lancet |volume=1 |issue=8273 |pages=643–7 |year=1982 |month=March |pmid=6121964 |doi=10.1016/S0140-6736(82)92201-2}}</ref> and was the first to develop tetrathiomolybdate for clinical use.<ref>{{cite journal |author=Harper PL, Walshe JM |title=Reversible pancytopenia secondary to treatment with tetrathiomolybdate |journal=Br. J. Haematol. |volume=64 |issue=4 |pages=851–3 |year=1986 |month=December |pmid=3801328 |doi=10.1111/j.1365-2141.1986.tb02250.x}}</ref> 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]].<ref name=Walshe1996/><ref>{{cite journal |author=Brewer GJ |title=Recognition, diagnosis, and management of Wilson's disease |journal=Proc. Soc. Exp. Biol. Med. |volume=223 |issue=1 |pages=39–46 |year=2000 |month=January |pmid=10632959 |url=http://www.ebmonline.org/cgi/content/full/223/1/39 |doi=10.1046/j.1525-1373.2000.22305.x}}</ref>
  +
  +
The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and 1990s by several research groups.<ref name="pmid8298639">{{cite journal |author=Bull PC, Thomas GR, Rommens JM, Forbes JR, Cox DW |title=The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene |journal=Nat. Genet. |volume=5 |issue=4 |pages=327–37 |year=1993 |pmid=8298639 |doi=10.1038/ng1293-327}}</ref><ref name="pmid8298641">{{cite journal |author=Tanzi RE, Petrukhin K, Chernov I, ''et al.'' |title=The Wilson disease gene is a copper transporting ATPase with homology to the Menkes disease gene |journal=Nat. Genet. |volume=5 |issue=4 |pages=344–50 |year=1993 |pmid=8298641 |doi=10.1038/ng1293-344}}</ref>
   
 
==References==
 
==References==
''Original text is from a [[public domain]] source found at: http://www.niddk.nih.gov/health/digest/summary/wilson/wilson.htm ''
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{{reflist|2}}
<div class="references-small">
 
<references />
 
</div>
 
   
 
==External links==
 
==External links==
 
* [http://www.wilsonsdisease.org/ Wilson's disease association international]
 
* [http://www.wilsonsdisease.org/ Wilson's disease association international]
* [http://www.wilsons-disease.org.uk/ Wilson's disease UK]
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* [http://www.wilsonsdisease.org.uk/ Wilson's disease UK]
  +
* [http://www.childliverdisease.org/ Children's Liver Disease Foundation] (UK)
  +
* [http://www.medicalgenetics.med.ualberta.ca/wilson/index.php Wilson Disease Mutation Database] ([[Human Genome Organisation|HUGO]])
 
* {{WhoNamedIt|synd|1818|Wilson's disease}}
 
* {{WhoNamedIt|synd|1818|Wilson's disease}}
 
* {{NLM|wilsondisease|Wilson disease}}
 
* {{NLM|wilsondisease|Wilson disease}}
 
* {{GeneTests|wilson|Wilson Disease}}
 
* {{GeneTests|wilson|Wilson Disease}}
* [http://www.childliverdisease.org/ Children's Liver Disease Foundation] - The only organisation in the UK dedicated to fighting childhood liver disease. The charity provides support to affected families, helps to educate healthcare professionals and the public, and funds vital research
 
   
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{{Mineral metabolic pathology}}
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{{CNS diseases of the nervous system}}
   
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[[Category:Genetic disorders]]
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[[Category:Autosomal recessive disorders]]
 
[[Category:Rare diseases]]
 
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Latest revision as of 07:38, May 20, 2010

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Wilson disease
Classification and external resources
Template:Px
Mutations in the ATP7B gene are present in the majority of patients with Wilson's disease.
ICD-10 E830
ICD-9 275.1
OMIM 277900
DiseasesDB 14152
MedlinePlus 000785
eMedicine med/2413 neuro/570 ped/2441
MeSH D006527

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.[1]

The condition is due to mutations 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 carriers). If a child inherits the gene from both parents, they may develop Wilson's disease. Symptoms usually appear between the ages of 6 and 20 years, but cases in much older patients have been described. Wilson's disease occurs in 1 to 4 per 100,000 people.[1] Wilson's disease is named after Dr. Samuel Alexander Kinnier Wilson (1878-1937), the British neurologist who first described the condition in 1912.[2]

Signs and symptomsEdit

The main sites of copper accumulation are the liver and the brain, and consequently liver disease and neuropsychiatric symptoms are the main features that lead to diagnosis.[1] Patients 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 patients, when tested, turn out to have been experiencing symptoms of the condition but haven't received a diagnosis.[3]

Liver diseaseEdit

Liver disease may present as tiredness, increased bleeding tendency or confusion (due to hepatic encephalopathy) 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, splenomegaly (enlargement of the spleen) and ascites (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 patients 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.[1]

About 5% of all patients 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 patient develops hepatic encephalopathy (confusion, coma, seizures and finally life-threatening swelling of the brain).[1]

Neuropsychiatric symptomsEdit

About half the patients with Wilson's have neurological or psychiatric problems. Most patients initially have mild cognitive deterioration and clumsiness, as well as changes in behavior. Specific neurological symptoms then follow, often in the form of parkinsonism (increased rigidity and slowing of routine movements) 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). Seizures and migraine appear to be more common in Wilson's disease.[1]

Psychiatric problems due to Wilson's disease may include behavioral changes, depression, anxiety and psychosis.[1]

Other organ systemsEdit

File:Kayser-Fleischer ring.jpg
A Kayser-Fleischer ring in a patient with symptoms suggestive of Wilson's disease

Various medical conditions have been linked with copper accumulation in Wilson's disease:

DiagnosisEdit

Brain structure
Location of the basal ganglia, the part of the brain affected by Wilson's disease
Dr Joe KiffAdded by Dr Joe Kiff

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 patients 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.[1] Alkaline phosphatase levels are relatively low in patients with Wilson's-related acute liver failure.[4] 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.[5] MRI may also demonstrate the characteristic "face of the giant panda" pattern.[6]

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.[1]

CeruloplasminEdit

File:PBB Protein CP image.jpg
Ceruloplasmin

Levels of ceruloplasmin are abnormally low (<0.2 gram/liter) in 80-95% of cases.[1] 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.[1][5]

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.[5]

Serum and urine copperEdit

Serum copper is paradoxically low but urine copper are 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.[1] High urine copper levels are not unique to Wilson's disease; they are sometimes observed in autoimmune hepatitis and in cholestasis (any disease obstructing the flow of bile from the liver to the small bowel).[5]

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.[5]

Liver biopsyEdit

Once other investigations have indicated Wilson's disease, the ideal test is the removal of a small amount of liver tissue through a liver biopsy. 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.[1]

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.[5]

Genetic testingEdit

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.[1]

GeneticsEdit

Autorecessive
Wilson's disease has an autosomal recessive pattern of inheritance.
Dr Joe KiffAdded by Dr Joe Kiff
Main article: ATP7B

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.[1] Mutations can be detected in 90% of patients. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. 10% have no detectable mutation.[3]

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.[1][7]

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.[8] A role for the ApoE gene was initially suspected but could not be confirmed.[7]

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 patients have no family history of the condition.[7] People with only one abnormal gene are called carriers (heterozygotes) and may have mild, but medically insignificant, abnormalities of copper metabolism.[5]

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.[7]

PathophysiologyEdit

File:Copper metabolism.png
Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.

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.[7]

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.[7]

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.[7]

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.[9]

Treatment Edit

Medical treatmentEdit

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. In general, a diet low in copper-containing foods (mushrooms, nuts, chocolate, dried fruit, liver, and shellfish) is recommended.[1]

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% of patients 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.[1][5] Patients 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.[5] A further agent with known activity in Wilson's disease is tetrathiomolybdate. This is still regarded as experimental,[5] although some studies have shown a beneficial effect.[1]

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.[5]

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.[10]

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.[5]

Liver transplantationEdit

Liver transplantation is the only 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 patients with fulminant liver failure who fail to respond to medical treatment, or in patients with advanced chronic liver disease. Liver transplantation is avoided in severe neuropsychiatric illness, in which its benefit has not been demonstrated.[1][5]

Other speciesEdit

Hereditary copper accumulation has been described in Bedlington Terriers,[11] where it generally only affects the liver. It is due to mutations in the COMMD1 (or MURR1) gene.[12] In patients with non-Wilsonian copper accumulation states (such as Indian childhood cirrhosis), no COMMD1 mutations could be detected to explain their genetic origin.[13]

HistoryEdit

The disease bears the name of the British physician Dr Samuel Alexander Kinnier Wilson (1878-1937), a neurologist who described the condition, including the pathological changes in the brain and liver, in 1912.[2] Wilson's work had been predated by, and drew on, reports from the German neurologist Dr Carl Westphal (in 1883), who termed it "pseudosclerosis", by the British neurologist Dr William Gowers (in 1888), and by Dr Adolph Strümpell (in 1898), who noted hepatic cirrhosis.[14] Prof John N. Cumings made the link with copper accumulation in both the liver and the brain in 1948.[15] The occurrence of hemolysis was noted in 1967.[16]

Cumings, and simultaneously the New Zealand neurologist Dr Derek Denny-Brown, working in the USA, first reported effective treatment with metal chelator British anti-Lewisite in 1951.[17][18] 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 available.[14][19] The first effective oral chelation agent, penicillamine, was discovered in 1956 by the British neurologist Dr John Walshe.[20] In 1982, Walshe also introduced trientine,[21] and was the first to develop tetrathiomolybdate for clinical use.[22] 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.[10][23]

The genetic basis of Wilson's disease and linkage to ATP7B mutations was elucidated in the 1980s and 1990s by several research groups.[24][25]

ReferencesEdit

  1. 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 1.14 1.15 1.16 1.17 1.18 1.19 1.20 1.21 1.22 1.23 Ala A, Walker AP, Ashkan K, Dooley JS, Schilsky ML (2007). Wilson's disease. Lancet 369 (9559): 397–408.
  2. 2.0 2.1 Kinnier Wilson SA (1912). Progressive lenticular degeneration: a familial nervous disease associated with cirrhosis of the liver. Brain 34 (1): 295–507.
  3. 3.0 3.1 3.2 Merle U, Schaefer M, Ferenci P, Stremmel W (2007). Clinical presentation, diagnosis and long-term outcome of Wilson's disease: a cohort study. Gut 56 (1): 115–20.
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