conspectus of researchon copper metabolism and requirements

2014 KARL E. MASON
bance, in certain cases at least, may not be
an abiotrophy but a condition of chronic
copper toxicity reflecting an inborn error
in copper metabolism. The results of
penicillamine treatment, said to be in
progress, and further exploration of these
observations by others, will be anticipated
with much interest.
There has also been described, in three
brothers, a hereditary disorder character
ized by dementia, spastic dysarthria, verti
cal eye movement paresis, gait disturbance,
splenomegaly and an abnormal metabolism
of copper (851). The disorder is prepubertal
in onset and progresses slowly
over many years. Copper kinetic studies
the unique combination of dementia,
splenomegaly, and abnormalities of speech,
vision and gait favor the view that this
condition represents a new syndrome dis
tinct from Wilson's disease. As far as can
be determined, no comparable cases have
since been reported. Both abnormalities
may possibly prove to be variants of Wil
son's disease.
Wilson's disease is not the only disorder
in which high liver levels of copper occur.
Chronic active liver disease closely resem
bles Wilson's disease in changes in hepatic
function and morphology, but can be dif
ferentiated from the latter in that ceruloplasmin
levels are elevated in about 50 %
of the cases and not below normal levels
in others (442), and the cupriuria after
penicillamine treatment is comparable to
that of normal individuals (473).
One other liver disease requires special
consideration. Levels of liver copper quite
comparable to and even greater than those
found in Wilson's disease occur in pri
marily biliary cirrhosis (215, 369, 721, 722,
862), a chronic, slowly progressive disease
with evidence of extrahepatic biliary ob
struction (223). Unlike the situation in
Wilson's disease, plasma clearance and
liver uptake of intravenous 84Cu are normal
(721). Similar conclusions were reached
by Fleming et al. (215) on the basis of
other evidence, including a new observa
tion that patients with primary biliary cir
rhosis also had significantly increased levels
of copper in the renal cortex and spleen.
In a study involving an extensive evalua
tion of 81 patients with primary biliary
cirrhosis, Kayser-Fleischer rings were found
in three cases, and also in another patient
with chronic active liver disease (216). In
the three patients mentioned, copper in
serum, urine and liver were significantly
elevated, resembling conditions seen in
Wilson's disease except for the high serum
copper and capacity to incorporate radiocopper
into ceruloplasmin. Concentration
of liver copper above a specified level of
250 /Ag/g of dry tissue, previously consid
ered as one of the four or five criteria for
diagnosis of Wilson's disease, now appears
to have limited value with accumulated
indicate similarities to those of hétérozyevidence
that such elevated concentrations
gote carriers of Wilson's disease. However, occur in the two types of liver disease just
mentioned. Furthermore, the presence of
Kayser-Fleischer rings can no longer be
considered pathognomonic of Wilson's
disease.
HYPOCUPREMIA
Previous sections have dealt with
Menkes' syndrome and states of copper de
ficiency in premature infants in which low
blood levels of copper, especially of cerulo
plasmin, are associated with various other
manifestations of copper deficiency. States
of hypocupremia without any evidence of
dietary copper deficiency characterize Wil
son's disease and occur, somewhat in
frequently, in a variety of other metabolic
and disease situations. Certain of these
justify recording.
The terms "hypocupremia" and "hypercupremia"
were introduced by Sachs et al.
(655) whose excellent review of early
studies on copper and iron in human blood,
and their newer contributions, are worthy
of note. Hypocupremia is defined as a
serum copper level of 80 ¿ig/100ml or less
(106). Since 93% of serum copper is nor
mally bound to ceruloplasmin, hypocu
premia must of necessity be synonymous
with hypoceruloplasminemia, except in un
usual circumstances. A syndrome charac
terized by hypocupremia, hypoferremia,
hypoproteinemia, edema and hypochromatic
anemia has been described in infants
and children and attributed to either a
dietary deficiency of copper and iron, with
hypoproteinemia considered a secondary
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