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Wilson’s disease is a human copper storage disease.
Wilson’s results in the accumulation of toxic levels of
copper in mainly the liver and secondarily in other organs such
as the kidneys, brain, and cornea. The disease is caused by a mutation
in the ATP7B gene, which codes for
a protein that facilitates the incorporation of copper into proteins
(such as ceruloplasmin) and also the transportation of copper into
vesicles that allow it to be secreted in bile.1 The critical
effect of a mutation in ATP7B is diminished
copper secretion into bile, which leads to excess copper accumulation
in the hepatocyte. The disease related to this defect therefore
involves toxicity to the liver with clinical disease that may range
from abnormal liver function tests to fulminant hepatic failure
and cirrhosis.
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Wilson’s is an autosomal recessive disease with an estimated
incidence of 1:30,000 live births internationally.2 The
most common presentation is in the second decade of life with hepatic
or hematologic symptoms (40–60%). The remaining
patients present with neurologic (~30%)
or psychiatric (10%) symptoms in their third or fourth
decade.2
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In normal human copper metabolism, the dietary intake and absorption
of copper is in excess of physiologic needs. The estimated daily
copper requirement for an adult is 1.3–1.7 mg, whereas the
normal daily Western copper intake is 2–5 mg of copper.3,4 The
estimated efficiency of copper absorption in the stomach and small
intestine is approximately 40–60%. Therefore,
the amount of copper absorbed by the intestine and retained in the body
must be regulated to prevent accumulation of excess copper—which
is toxic. The main regulatory system for maintaining copper balance
in the body is the excretion of up to 80% of absorbed copper
in the bile5,6 (Figure 25–1). Up to 1.2–1.7
mg/day of copper is excreted in the bile daily.6,7 There
are also several chemical factors that impair intestinal copper
absorption, such as excess zinc or ascorbic acid.8–10
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Dietary copper is absorbed into the small intestine epithelial
cells where it complexes either to the protein metallothionein or
to amino acids for transport into the portal circulation. Metallothionein also
forms complexes with zinc and cadmium, though less strongly than
copper. Zinc stimulates metallothionein synthesis in the intestinal
cell. In doing so, it promotes retention of metallothionein-bound
copper in the enterocyte that will then be excreted in the feces
when the enterocyte is shed.11 It is on this basis that
zinc was postulated to reduce intestinal copper absorption and became
a modality of treatment for Wilson’s.
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Once in the portal circulation, the copper complexes to albumin
or amino acids with only a small fraction remaining “free.” A
copper transporter (hCTR) for albumin-bound copper then transports the
copper into the hepatocyte....