Editing Wilson's disease (section)

==Diagnosis==
[[Image:Basal ganglia and related structures (2).svg|thumb|Location of the basal ganglia, the part of the brain affected by Wilson's disease]]

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 raised [[aspartate transaminase]], [[alanine transaminase]], and [[bilirubin]] levels. 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 those with Wilson's-related acute liver failure.<ref name="pmid3758940">{{cite journal |vauthors = 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|s2cid=24055787 |doi-access=free }}</ref> If neurological symptoms are seen, [[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="Roberts2003">{{cite journal |last1=Roberts |first1=Eve A. |last2=Schilsky |first2=Michael L. |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 |s2cid=263620 |doi-access=free }}</ref> MRI may also demonstrate the characteristic [[Face of the Giant Panda Sign|"face of the giant panda"]] pattern.<ref name=Panda>{{cite journal |vauthors=Das SK, Ray K |title=Wilson's disease: an update |journal=Nat Clin Pract Neurol |volume=2 |issue=9 |pages=482–93 |date=September 2006 |pmid=16932613 |doi=10.1038/ncpneuro0291 |s2cid=205340375 }}</ref>

No totally reliable test for Wilson's disease is known, 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 most accurate test is a [[liver biopsy]].<ref name=Ala/>

===Ceruloplasmin===
[[Image:PBB Protein CP image.jpg|thumb|Ceruloplasmin]]
Levels of ceruloplasmin are abnormally low (<0.2&nbsp;g/L) in 80–95% of cases.<ref name=Ala/>  It can be present at normal levels, though, 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=Roberts2003/> The combination of neurological symptoms, eye signs, 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=Roberts2003/>

===Serum and urine copper===
Serum copper is low, which may seem paradoxical given that Wilson's disease is a disease of copper excess. However, 95% of plasma copper is carried by ceruloplasmin, which is often low in Wilson's disease. Urine copper is elevated in Wilson's disease and 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=Roberts2003/>

In children, the following [[penicillamine]] test may be used: a 500&nbsp;mg oral dose of penicillamine is administered, and all urine collected for 24 hours. If the entire day's urine contains more than 1600&nbsp;μg (25&nbsp;μmol) of copper, it is a reliable indicator of Wilson's disease. This test has not been validated in adults.<ref name=Roberts2003/>

=== Slit-lamp examination ===
The eyes of the patient are examined using a [[slit lamp]] to look for [[Kayser–Fleischer ring]]s, which are strongly associated with Wilson's disease and are caused by copper deposition on the inner [[cornea]] in [[Descemet's membrane]].<ref name="Pandey"/>

===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 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/>

In the earlier stages of the disease, the biopsy typically shows 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=Roberts2003/>

===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, family members can be screened for the disease as part of [[clinical genetics]] family counseling.<ref name=Ala/> Regional distributions of genes associated with Wilson's disease are important to follow, as this can help clinicians design appropriate screening strategies. Since mutations of the ''ATP7B'' gene vary between populations, research and genetic testing done in countries such as the USA or United Kingdom can pose problems, as they tend to have more mixed populations.<ref>{{Cite journal|title = Regional distribution of mutations of the ATP7B gene in patients with Wilson disease: impact on genetic testing|journal = Human Genetics|date = 2006-06-22|issn = 0340-6717|pages = 151–159|volume = 120|issue = 2|doi = 10.1007/s00439-006-0202-5|language = en|first = Peter|last = Ferenci|pmid=16791614|s2cid = 10124665}}</ref>