Wilson's disease pathophysiology: Difference between revisions

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==Overview==
==Overview==
[[Copper]] is one of the essential elements for the [[human body]]. Copper must be absorbed and transported in order to function properly. Copper is transported bound to [[metallothionein]] or carried by [[ATOX1]] to the [[Golgi apparatus|trans-Golgi network]]. Impairment of copper incorportation in formation of [[ceruloplasmin]] will lead to increase the serum level of the [[copper]]. The increase of copper level will lead to accumulation of the excess amount in the [[liver]] and other organs. [[ATP7B]] [[gene mutation]] is found in the majority of the patients with Wilson's disease.
==Pathophysiology==
==Pathophysiology==


=== Normal copper transportation and metabolism ===
=== Normal copper transportation and metabolism ===
* [[Copper]] is one of the essential elements that is required daily in [[diet]] in a range of 1.5 to 2 mg.<ref name="pmid6280488">{{cite journal| author=Sandstead HH| title=Copper bioavailability and requirements. | journal=Am J Clin Nutr | year= 1982 | volume= 35 | issue= 4 | pages= 809-14 | pmid=6280488 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6280488  }}</ref>
* Copper is incorporated in number of important functions in the body. It functions as a component of  some [[enzymes]] as [[cytochrome c oxidase]], [[dopamine beta hydroxylase|dopamine β-hydroxylase]], [[superoxide dismutase]] and [[tyrosinase]].<ref name="pmid62804882">{{cite journal| author=Sandstead HH| title=Copper bioavailability and requirements. | journal=Am J Clin Nutr | year= 1982 | volume= 35 | issue= 4 | pages= 809-14 | pmid=6280488 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=6280488  }}</ref>
* In order to function appropriately, a significant proportion of [[copper]] must be absorbed and transported to the different site of actions. [[Stomach]] and [[duodenum]] are the main sites of absorption of copper then it binds [[albumin]] and transported to different [[Body tissue|body tissues]]. The excess copper is excreted as [[feces]] after being a part of the [[bile]].
* Copper is carried inside the [[cells]] by a transporter [[protein]] on the [[enterocyte|cells of the small bowel]] called [[SLC31A1|copper membrane transporter 1]] (CMT1). Others are bound to [[metallothionein]] where the rest is carried by [[ATOX1]] to the [[Golgi apparatus|trans-Golgi network]]. 
* Transportation of the [[copper]] to different [[Body tissue|body tissues]] is regulated by [[ATP7B|ATP7B gene]] in the [[hepatocytes]].
* [[ATP7B|ATP7B gene]] acts on transporting [[copper]] via two ways:<ref name="pmid17390257">{{cite journal| author=Pfeiffer RF| title=Wilson's Disease. | journal=Semin Neurol | year= 2007 | volume= 27 | issue= 2 | pages= 123-32 | pmid=17390257 | doi=10.1055/s-2007-971173 | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17390257  }}</ref><ref name="pmid9261163">{{cite journal| author=Hung IH, Suzuki M, Yamaguchi Y, Yuan DS, Klausner RD, Gitlin JD| title=Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae. | journal=J Biol Chem | year= 1997 | volume= 272 | issue= 34 | pages= 21461-6 | pmid=9261163 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9261163  }} </ref>
** In the [[Trans Golgi network|trans-golgi network]]: Formation of [[ceruloplasmin]] (which is secreted into the [[blood]]) by adding the copper to the apoceruloplasmin.
** In the [[cytoplasmic]] [[vesicles]]: Excretion of the excess copper into [[Bile|the bile]] by [[exocytosis]] against the [[hepatocytes]] memebrane.
[[Image:Copper metabolism.png|thumb|center|framed|Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper. Source:By en:User:Jfdwolff - Copper Metabolism, English Wikipedia, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7777267]]


=== Pathogenesis ===
=== Pathogenesis ===
[[Image:Brain structure.gif|center|framed|Location of the basal ganglia, the part of the brain affected by Wilson's disease]]
* The following table includes the main mechanisms that play an important role in pathogenesis of Wilson's disease.
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]].
{| class="wikitable"
 
!Impaired copper metabolism
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.
!Role in Wilson's disease pathogenesis
 
|-
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.
|Impaired [[copper]] incorporation
 
|
 
* Failure of the copper to be incorporated into apoceruloplasmin leads to accumulation of the [[copper]] in the [[hepatocytes]] and different [[Body tissue|body tissues]] and [[organs]].
[[Image:Copper metabolism.png|center|framed|Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper.]]
* [[Ceruloplasmin]] level may be decreased as a result of impaired copper incorporation. However, it is not required to diagnose Wilson's disease.  
 
|-
 
|Copper accumulation in hepatocytes
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>
|
 
* The copper accumulates in the [[hepatocytes]] and ends up into [[Liver cells|liver cell]] [[injury]].  
==Genetics==
|-
[[Image:autorecessive.svg|thumb|left|Wilson's disease has an autosomal recessive pattern of inheritance.]]
|Extrahepatic copper accumulation
{{main|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-ATPase|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.
* Copper accumulation will eventually lead to copper deposition in other organs like [[Brain|the brain]].  
 
* The [[urinary]] excretion of the [[copper]] will not be able to decrease the serum levels and the deposition increases over time ending by the damage of the other [[organs]] especially the [[brain]].  
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 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.<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>
|}
 
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" />
 
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.<ref name="deBie2007" /> 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 the ''[[Keratin 8|KRT8]]'' and the ''[[Keratin 18|KRT18]]'' gene.<ref name="deBie2007" />


==Other species==
== Genetics ==
Hereditary copper accumulation has been described in Bedlington Terriers,<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>
* [[ATP7B]] [[gene mutation]] is the main cause of [[copper]] transportation impairment and Wilson's disease.  
* ATP7B gene placed on [[chromosome 13]] and is expressed primarily in the [[liver]], [[kidney]], and [[placenta]].
* Wilson's disease [[ATP7B]] [[gene mutation]] is inhereted in an [[Autosomal recessive|autosomal recessive pattern]]. The majority of the patients have no family history.  


== Associated conditions ==
== Associated conditions ==
* Wilson's disease may be associated with the following conditions:<ref name="de BieMuller2007">{{cite journal|last1=de Bie|first1=P|last2=Muller|first2=P|last3=Wijmenga|first3=C|last4=Klomp|first4=L W J|title=Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes|journal=Journal of Medical Genetics|volume=44|issue=11|year=2007|pages=673–688|issn=1468-6244|doi=10.1136/jmg.2007.052746}}</ref>
** [[Fulminant liver failure]]
** [[Liver cirrhosis|Cirrhosis]]
** [[Aceruloplasminaemia]]


==Gross pathology==
==Gross pathology==
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</div>  
</div>  


==Microscopic pathology==  
==Microscopic pathology==
* Histological examination of a [[Liver biopsy|liver]] biopsy may show the following:<ref name="pmid167753002">{{cite journal| author=Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW et al.| title=MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation. | journal=AJNR Am J Neuroradiol | year= 2006 | volume= 27 | issue= 6 | pages= 1373-8 | pmid=16775300 | doi= | pmc= | url=https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16775300  }}</ref>
** Mild [[steatosis]] which is considered an early histological feature
** Glycogenated [[hepatic]] [[nuclei]]
** [[Hepatocellular Disease|Hepatocellular]] necrosis
** Autoimmune hepatitis histologic features
** Fibrosis and cirrhosis (macronodular or micronodular) in advanced cases
** Fulminant liver falilure features which include:
*** Hepatocellular degenration
*** Parenchymal collapse


==References==
==References==
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Ahmed Elsaiey, MBBCH [2]

Overview

Copper is one of the essential elements for the human body. Copper must be absorbed and transported in order to function properly. Copper is transported bound to metallothionein or carried by ATOX1 to the trans-Golgi network. Impairment of copper incorportation in formation of ceruloplasmin will lead to increase the serum level of the copper. The increase of copper level will lead to accumulation of the excess amount in the liver and other organs. ATP7B gene mutation is found in the majority of the patients with Wilson's disease.

Pathophysiology

Normal copper transportation and metabolism

Normal absorption and distribution of copper. Cu = copper, CP = ceruloplasmin, green = ATP7B carrying copper. Source:By en:User:Jfdwolff - Copper Metabolism, English Wikipedia, Public Domain, https://commons.wikimedia.org/w/index.php?curid=7777267

Pathogenesis

  • The following table includes the main mechanisms that play an important role in pathogenesis of Wilson's disease.
Impaired copper metabolism Role in Wilson's disease pathogenesis
Impaired copper incorporation
  • Failure of the copper to be incorporated into apoceruloplasmin leads to accumulation of the copper in the hepatocytes and different body tissues and organs.
  • Ceruloplasmin level may be decreased as a result of impaired copper incorporation. However, it is not required to diagnose Wilson's disease.
Copper accumulation in hepatocytes
Extrahepatic copper accumulation
  • Copper accumulation will eventually lead to copper deposition in other organs like the brain.
  • The urinary excretion of the copper will not be able to decrease the serum levels and the deposition increases over time ending by the damage of the other organs especially the brain.

Genetics

Associated conditions

Gross pathology

Images courtesy of Professor Peter Anderson DVM PhD and published with permission © PEIR, University of Alabama at Birmingham, Department of Pathology

  • Liver cirrhosis and enlarged gall bladder in Wilson's disease.

    Liver cirrhosis and enlarged gall bladder in Wilson's disease.

  • Liver cirrhosis and enlarged gall bladder in Wilson's disease.

    Liver cirrhosis and enlarged gall bladder in Wilson's disease.

  • Lung, hemorrhagic bronchopneumonia, Wilson's disease

    Lung, hemorrhagic bronchopneumonia, Wilson's disease

  • Spleen, congestion. Wilson's disease

    Spleen, congestion. Wilson's disease

Microscopic pathology

  • Histological examination of a liver biopsy may show the following:[6]
    • Mild steatosis which is considered an early histological feature
    • Glycogenated hepatic nuclei
    • Hepatocellular necrosis
    • Autoimmune hepatitis histologic features
    • Fibrosis and cirrhosis (macronodular or micronodular) in advanced cases
    • Fulminant liver falilure features which include:
      • Hepatocellular degenration
      • Parenchymal collapse

References

  1. ↑ Sandstead HH (1982). "Copper bioavailability and requirements". Am J Clin Nutr. 35 (4): 809–14. PMID 6280488.
  2. ↑ Sandstead HH (1982). "Copper bioavailability and requirements". Am J Clin Nutr. 35 (4): 809–14. PMID 6280488.
  3. ↑ Pfeiffer RF (2007). "Wilson's Disease". Semin Neurol. 27 (2): 123–32. doi:10.1055/s-2007-971173. PMID 17390257.
  4. ↑ Hung IH, Suzuki M, Yamaguchi Y, Yuan DS, Klausner RD, Gitlin JD (1997). "Biochemical characterization of the Wilson disease protein and functional expression in the yeast Saccharomyces cerevisiae". J Biol Chem. 272 (34): 21461–6. PMID 9261163.
  5. ↑ de Bie, P; Muller, P; Wijmenga, C; Klomp, L W J (2007). "Molecular pathogenesis of Wilson and Menkes disease: correlation of mutations with molecular defects and disease phenotypes". Journal of Medical Genetics. 44 (11): 673–688. doi:10.1136/jmg.2007.052746. ISSN 1468-6244.
  6. ↑ Kim TJ, Kim IO, Kim WS, Cheon JE, Moon SG, Kwon JW; et al. (2006). "MR imaging of the brain in Wilson disease of childhood: findings before and after treatment with clinical correlation". AJNR Am J Neuroradiol. 27 (6): 1373–8. PMID 16775300.

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