conspectus of researchon copper metabolism and requirements

2004 KARL E. MASON
number of informative reviews (461, 533,
666, 843).
DIETARY COPPER DEFICIENCY
There appear repeated statements in the
literature that in view of the ubiquitous
occurrence of copper in foods of every
type, and lack of evidence of any recog
nized manifestations of copper deficiency
such as commonly observed after dietary
depletion of copper in experimental ani
mals or under natural conditions in farm
animals, man appears to be free of hazards
of a state of copper deficiency. However,
there has developed convincing evidence
that a copper deficiency state can occur in
man, even though it may be of rare oc
currence and as the result of rather special
types of situations.
A syndrome characterized by hypocupremia,
hypoferremia, hypoproteinemia,
edema and hypochromic anemia, respon
sive to oral copper but not to iron, has
been observed in infants fed diets limited
largely to milk (432, 437, 758, 796, 797,
874). In certain cases, especially those of
Ulstrom et al. (796, 797), a fundamental
defect in protein metabolism at the cellular
level may have been a primary factor,
rather than exhaustion of neonatal copper
stores (874). The fact that infants 6 to 18
months of age usually have been involved
suggests a relation to periods of life when
initial liver storage of copper has been
depleted, combined with prolonged main
tenance on milk diets and increased de
mands for copper during a period of rapid
growth. However, the possibility of de
grees of protein depletion sufficient to im
pair retention of dietary copper deserved
consideration.
Maintenance of two infants (one 8 days
old with multiple congenital anomalies,
and the other 10 months old) for 4 to 5
months on a milk diet identical to one
which produced copper deficiency in pig
lets, caused neither anemia nor hypocupremia
(101). Comparable results were
obtained in the studies of Wilson and
Lahey (854) involving seven premature
infants with mean body weight of 1.24 kg
fed a similar milk diet for 7 to 10 weeks.
It was concluded that small premature in
fants fed a diet providing approximately
15 /xg/kg/day of elemental copper over a
2 to 3-month period do not differ, by any
of the criteria used, from prematures fed
five or more times this amount. However, it
should be recognized that at this period
such infants could be utilizing liver stores
of copper, and that the depletion period
was much shorter than that required for
production of a deficiency state in piglets
with a relatively more rapid rate of growth.
Not until 1964 was a state of dietary
copper deficiency documented in humans
when Cordano et al. (126, 128) reported
finding in infants, recovering from maras
mus on exclusive milk diets, deficiency
manifestations (anemia, decreased plasma
copper and ceruloplasmin levels, intermit
tent neutropenia, severe osteoporosis and
pathological fractures) quite comparable
to those observed after experimental cop
per deficiency in pigs (436). Similar find
ings were observed in a 6-year old child
with severe chronic intestinal malabsorption,
who gave a dramatic response to cop
per therapy (127). In a later report,
Graham and Cordano (276) state that in a
series of 173 infants suffering from severe
malnutrition and chronic diarrhea, admit
ted to the British American Hospital, Lima,
Peru, over a period of 6 years, 62 instances
of copper deficiency were identified, of
which 44 were judged to have been de
pleted of copper prior to admission. The
peak incidence was at 7 to 9 months of
age. Responses to oral copper therapy in
dicated that repletion of total serum cop
per was more important than restoration of
ceruloplasmin in correction of the defi
ciency state (352). Instances of copper de
pletion have also been observed in infants
with chronic diarrhea in the United States
(354).
There have also appeared more recent
reports of neonatal copper deficiency in a
premature infant 3 months old (17), in
three very small premature infants during
their third month of life (280), in a pre
mature infant 3 months of age (700), and
in a premature infant at 6 months of age
(25). Neutropenia, low plasma ceruloplas
min and osteoporosis have been among the
manifestations regularly observed. Favor
able response to oral copper has usually
been reported. Although none of the in-
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