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Assays / Trace
Metals/ Copper
Copper is now well established as an essential trace element;
the estimated safe and adequate adult daily intake is 2.5 - 3 mg/day
(39 -47 µmol). Copper - containing metalloenzymes are important
in iron and catecholamine metabolism, haemoglobin, elastin and collagen
synthesis and free radical scavenging. About 30% of ingested copper
is absorbed in the intestine, bound to albumin and transported to
the liver, where it is stored. The major circulating form is the
blue glycoprotein, caeruloplasmin, synthesised in the liver, which
contains 6 - 8 atoms of copper per molecule. The functions of this
protein are still unclear, but it is important in iron metabolism
as a ferroxidase and may have a role in regulating copper transport.
It is an acute phase reactant and can increase greatly in response
to infection, injury, chronic inflammatory conditions or steroid
hormones (pregnancy, certain contraceptive pills and oestrogen therapy).
Serum copper and caeruloplasmin are both increased in these circumstances,
as caeruloplasmin normally carries about 95% of the circulating
copper. Excess copper is excreted in the bile, only small amounts
being found in urine, unless renal damage is present, or substances
which bind copper are excreted.
Deficiency
Copper deficiency presents as a microcytic
hypochromic anaemia with marked neutropenia, which is resistant
to iron therapy. Children and neonates on diets deficient in copper
have ineffective collagen synthesis, and may develop bone disease.
As the liver contains substantial stores of copper, frank clinical
copper deficiency is unusual, but has been reported in malnourished
children and in adults on long term parenteral nutrition. Reduced
copper absorption is common in diarrhoea and when zinc intake is
increased. Subclinical copper deficiency may be more widespread
then previously thought and has been suggested as a risk factor
for cardiovascular disease through reduced antioxidant activity
altered lipoprotein and catecholamine metabolism and vascular changes.
The rare sex linked recessive disorder, Menkes 'steely hair' disease,
is characterised by a failure of copper transport across the intestinal
mucosa. The hair changes are similar to those occurring in copper
deficient sheep. Although copper levels are low in brain and liver,
copper accumulates in many tissues of the body. The intake into
cells appears to be normal but there is defective utilisation intracellularly.
The condition is therefore one of functional copper deficiency as
a result of impaired function of copper dependent enzymes. Patients
show mental retardation, depigmentation, severe anaemia, hypotonia
and scorbutic changes in bone. Serum copper and caeruloplasmin concentrations
are extremely low; intravenous treatment with copper histidine may
be effective if initiated early in life. Diagnosis can be confirmed
by measuring the accumulation of copper in cultured fibroblasts
from skin biopsy, or prenatally, by measuring the copper content
of chorionic villi in the first trimester.
Toxicity
Wilson's disease (hepatolenticular degeneration)
is an autosomal recessive disorder, the frequency being of the order
of 1 in 100,000 live births. Copper cannot be excreted via the bile,
or incorporated into caeruloplasmin, and consequently accumulates
within the liver. Later it is probable that the copper 'overflows'
and accumulates more slowly in other tissues, especially the brain.
The classical presentation is of adults with progressive neurological
symptoms, low serum concentrations of copper and caeruloplasmin,
raised urinary copper excretion, and characteristic copper deposits
in the corneas (Kayser-Fleischer rings). It is now recognised that
children and adolescents frequently present with a variety of hepatic
symptoms including fulminant hepatic failure.
Depending on the stage of the disorder, plasma copper
may be normal or even increased, as in acute hepatic conditions,
and caeruloplasmin, an acute phase reactant, normal. Measurement
of the liver copper content, or of the urinary output of copper
following a penicillamine challenge may be necessary to diagnose
difficult cases.
Acute ingestion of copper salts produces nausea, vomiting,
diarrhoea, circulatory collapse and intravascular haemolysis. Cases
have been reported following the ingestion of copper sulphate solutions,
either deliberately or by accident; in patients on maintenance haemodialysis
following leaching of the element from copper containing dialysis
membranes (Cuprophan); inhalation of fumes from the burning of chromate-copper-arsenic
(CCA) treated wood; use of Bordeaux mixture for crop spraying. In
situations of acute toxicity serum copper concentration will be
high, but the caeruloplasmin concentration will be normal.
Chronic poisoning with copper leads to gross hepatic
copper overload with severe liver disease in young children. Indian
childhood cirrhosis has been ascribed to storage of milk in copper
vessels and there are reports of poisoning in young children as
a result of high copper content in well water. Liver copper content
in such cases can exceed that found in overload due to Wilson's
disease but the storage mechanisms and histological appearance will
be different.
The copper content of betel nuts has been suggested
as the causative agent for the oral fibrosis found in habitual chewers
of this fruit.
Laboratory Indices of Copper Status
Some of the problems of interpreting the serum
copper concentration, particularly in the diagnosis of Wilson's
disease, have been mentioned above. It is always advisable to measure
serum copper and caeruloplasmin and the urinary copper excretion.
'Free' or non-caeruloplasmin copper can be derived from the serum
measurements. This increases as Wilson's disease progresses, but
is also raised in other liver disorders. It is of diagnostic value
in fulminant hepatic failure due to Wilson's disease and in copper
poisoning. Measuring urinary copper excretion before and during
administration of 2 x 500 mg oral doses of penicillamine at 12 hour
intervals can help to distinguish children with Wilson's disease
(over 25 µmol/24h post penicillamine) from those with liver
disease due to other causes. Determination of copper content and
the histological examination of a needle biopsy of liver is frequently
of value in establishing the diagnosis. However, bile is a major
copper excretion route and biliary impairment in other liver conditions,
such as primary biliary cirrhosis, may result in elevated liver
copper.
In neonates, serum copper and caeruloplasmin levels
are low and rise during the early weeks of life, reaching adult
levels after 1 to 2 years. This makes the diagnosis of Wilson's
disease difficult during the first six months. Copper concentrations
which fail to rise above 5 µmol/L after the first few weeks
may indicate copper deficiency.
Copper deficiency may be masked by increased caeruloplasmin
synthesis as part of an 'acute phase' response to infection, injury
or chronic inflammatory disease. The degree of such a response should
be considered. An increase in caeruloplasmin following copper supplementation
may be a method for confirming deficiency.
Liver Biopsies (or other tissues) for Copper Determination.
Protocol for collection and transport is given
in the COPPER - yellow pages.
References:
Danks DM. Disorders of copper transport. In:
Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic Basis
of Inherited Disease, 7th edn. New York: McGraw-Hill, 1995: 2211-35
Taylor A. Detection and monitoring for disorders of
essential trace elements. Annals of Clinical Biochemistry 1996;
33: 486-510
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