Editing Wilson's disease (section)

==Pathophysiology==
[[Image:Copper metabolism.png|thumb|Normal absorption and distribution of copper: Cu = copper, CP = [[ceruloplasmin]], green = ATP7B carrying copper]]

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 enters the body through the [[Human gastrointestinal tract|digestive tract]]. A transporter protein on the [[enterocyte|cells of the small bowel]], [[SLC31A1|copper membrane transporter 1]] (Ctr1; SLC31A1), 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]] (Menkes' protein) 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, ATP7B 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 apo-ceruloplasmin) and is rapidly degraded in the bloodstream.<ref name=deBie2007/>

When the amount of copper in the liver overwhelms the proteins that normally bind it, it causes oxidative damage to the liver 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 and play 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/>

Why Wilson's disease causes hemolysis is unclear, but various lines of evidence suggest that a high level of free (nonceruloplasmin-bound) copper may be directly affecting the oxidation of [[hemoglobin]], or inhibiting the energy-supplying enzymes in [[red blood cell]]s, or causing direct damage to [[cell membrane]]s.<ref>{{cite book |last=Lee |first=GR |veditors=Lee GR, Foerster J, Lukens J |title=Wintrobe's clinical hematology |edition=10th |volume=1 |year=1999 |publisher=Williams & Wilkins |isbn=978-0-683-18242-2 |pages=[https://archive.org/details/wintrobesclinica0000unse/page/1298 1298] |chapter=Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents |display-editors=etal |chapter-url=https://archive.org/details/wintrobesclinica0000unse/page/1298 }}</ref>