conspectus of researchon copper metabolism and requirements

2038 KARL E. MASON
and other organs of the fetus and infant.
An intrauterine defect could explain why
even in infants with early postnatal diag
nosis, therapeutic measures of varied types
have done little more than improve serum
copper and ceruloplasmin levels, while the
disease process continues unabated. The
recent discovery and study of two genetic
animal models in mice with striking simi
larities to Menkes' disease, combined with
continued study of dietary copper defi
ciency in the rat and guinea pig, offer
challenging opportunities for further inves
tigation of the metabolic defect(s) under
lying this disease and some remote possi
bility of more effective therapeutic mea
sures than currently exist, even though
intervention in utero may be the only
recourse.
Mystery also still surrounds the primary
defect in Wilson's disease (hepatolenticu-
lar degeneration), an autosomal recessive
inborn error of metabolism first described
in 1912 and characterized by the accumu
lation of excessive and often toxic amounts
of copper in the liver, central nervous sys
tem, kidney and other tissues. Accumulat
ing evidence points to the liver as the site
of metabolic derangement, and decreased
biliary excretion of copper the basic reason
for the progressive increase of liver copper
to toxic levels. Hypotheses proposed sug
gest: 1) the presence in the liver, and
possibly in other affected tissues, of an
intracellular protein having greatly in
creased affinity for the binding of copper;
2) defects in a liver protein or peptide
serving in a specific "carrier mechanism"
for copper or, 3) defective intracellular
transport of copper secondary to dysfunc
tion of hepatocyte lysosomes. The further
pursuit of these concepts should open new
vistas concerning the metabolic defect in
Wilson's disease. As an example, recent
evidence of dramatic improvement in extrahepatic
manifestations of Wilson's dis
ease following orthoptic liver transplanta
tion also supports the concept that the
metabolic defect in Wilson's disease is
liver-based. For more than 20 years the
therapeutic use of D-penicillamine, a cop
per chelator, has led to slow clinical im
provement, especially when instituted in
early states of the disease. A real need
exists for an improved method for diag
nosis of asymptomatic cases of the disease,
replacing liver biopsy and radiocopper
studies, to permit earlier establishment of
therapeutic measures. The possible exist
ence of a more effective therapeutic agent
seems not to have been given the attention
deserved. There is recent evidence that at
least two liver diseases, primary biliary
cirrhosis and chronic active liver disease,
resemble Wilson's disease with respect to
elevated levels of liver copper. Whether in
these disorders benefits may be derived
from penicillamine therapy has not been
established.
In the development and practical appli
cation of total parenteral nutrition over the
past 10 years, isolated instances of states
of copper deficiency occurring in children
and adult man have emphasized the need
for more serious attention to the content
of copper and other trace elements in
parenteral solutions. Information gained
from experiences with parenteral nutrition
have given strong support to conclusions
reached by balance studies concerning the
minimal requirements of copper for infants
and adults. A much greater hazard has
been created by copper-contaminated tap
water or copper-containing valves and
stopcocks in conduits employed in hemodialysis,
due to the high toxicity of intra
venous copper. There are sporadic reports
of accidental and suicidal poisoning from
oral intake of copper salts. There is little
or no evidence of toxicity from industrial
sources.
Extensive evidence based upon the cop
per content of human milk (approximately
three times that of cow's milk ), copper bal
ance studies and experiences with total
parenteral nutrition indicate that copper
requirements for young full-term infants
are 0.025 to 0.05 mg/kg/day, and that
those for premature infants are somewhat
greater. Rather limited data, based largely
on balance studies, suggest requirements
in the range of 0.05 to 0.10 mg/kg/day for
young and adolescent children. There is a
serious lack of information concerning
copper requirements of teenagers, and
especially pregnant teenagers. It has long
been felt that an adult man requires 2.0
to 2.5 mg copper daily. Balance studies of
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