Wilson's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
Pathophysiology
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 tometallothionein 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.[1]
Genetics
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% of patients. Most (60%) are homozygous for ATP7B mutations (two abnormal copies), and 30% have only one abnormal copy. 10% 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 histidineby a glutamine at position 1069 in the gene) 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.[2]
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.[3] A role for the ApoE gene was initially suspected but could not be confirmed.[2]
The condition is inherited in an autosomal recessive pattern, which means both copies of the gene have mutations. 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.[2] 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, but ICC has been linked to mutations in theKRT8 and the KRT18 gene.[2]
References
- ↑ Lee, GR (1999). "Chapter 48: acquired hemolytic anaemias resulting from direct effects of infectious, chemical or physical agents". In Lee GR, Foerster J, Lukens J; et al. Wintrobe's clinical hematology. vol 1 (10th ed.). Williams & Wilkins. p. 1298. ISBN 0-683-18242-0.
- ↑ 2.0 2.1 2.2 2.3 de Bie P, Muller P, Wijmenga C, Klomp LW (2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". J. Med. Genet. 44 (11): 673–88. doi:10.1136/jmg.2007.052746. PMID 17717039. Unknown parameter
|month=ignored (help) - ↑ Grubenbecher S, Stüve O, Hefter H, Korth C (2006). "Prion protein gene codon 129 modulates clinical course of neurological Wilson disease". Neuroreport. 17 (5): 549–52. doi:10.1097/01.wnr.0000209006.48105.90. PMID 16543824.