conspectus of researchon copper metabolism and requirements

2012 KARL E. MASON
may reside in the hepatic cell lysosomes
(260, 261, 749, 755) whose catabolic func
tions and importance in transfer of copper
to the bile canaliculi are well recognized.
It appears that early in the disease copper
is diffusely distributed in hepatocytes, later
as more discrete granules, and that when
hepatic damage is more widespread it be
comes more localized in the lysosomes,
where it may be less toxic ( 261 ). Delay in
this uptake by lysosomes could be a key
factor in the defective liver transport of
copper in Wilson's disease (721). Ques
tions still remain as to whether abnormal
copper-binding proteins or lack of un
known cell enzymes involved in transfer
of copper to, or in release of copper from,
the lysosomes are responsible. The inter
esting observations of Goldfisher and Sternlieb
(161) have raised the hypothesis that
Wilson's disease may prove to be a "lysosomal
disease," as discussed in some detail
by Sternlieb et al. (749) and Strickland et
al. (755). f
Major results of reduced biliary excre
tion are increased copper accumulation in
hepatocytes, varying degrees of pathology,
jaundice and episodes of hemolytic anemia,
the latter being secondary to release of
copper from an overloaded and damaged
liver into the blood stream. If this release
is sudden, there can be severe damage to
circulating erythrocytes, resulting in repet
itive or fatal episodes of hemolytic anemia.
A recent report (516) tabulates pertinent
data on 18 reports involving 28 subjects.
Of these, six presented hemolysis prior to
any diagnosis of Wilson's disease and 20
showed evidence of hemolysis at the time
of diagnosis. Evidence of hepatic dysfunc
tion was noted in at least 22, whereas
neurological dysfunction was recognized in
only three or four. A more recent report of
two cases of fulminating hemolysis in
Wilson's disease calls attention to acute
renal failure as well as hepatic failure
(302). Hence, this hemolytic manifestation
of Wilson's disease has become a more
common phenomenon than previously rec
ognized. In view of the fact that there is
an associated marked increase in the cop
per content of erythrocytes and in the
number of Heinz bodies during periods of
crisis, hemolysis is attributed to increased
oxidative stress due to an excessive ac
cumulation of copper in the cells (155,
508). Whether this is primarily a mem
brane defect is still an open question
(516). It has been considered (102, 155,
508) a counterpart of the well known
"enzootic jaundice" in sheep, the history
and nature of which has been presented
by Underwood (798). This concept is
strongly supported by a recent study of
controlled, experimental copper poisoning
in sheep demonstrating extensive forma
tion of Heinz bodies, predominantly mem
brane-attached, as the first morphological
alteration observed (725). Hepatocellular
and renal tubular necrosis were also noted.
Therapy
The chance observation of Mandelbrote
et al. (485), in a study of copper mobiliza
tion in multiple sclerosis, that one of the
control subjects who was later found to
have Wilson's disease was greatly benefited
by treatment with BAL (/3,/3-dimercaptopropanol),
known to have properties of a
chelator, provided the first therapeutic
measure, introduced by Cumings in 1948
( 135). While daily intramuscular injections
proved effective in increasing the urinary
output of copper (39, 46, 135, 163), there
was no effect upon the aminoaciduria or
other clinical manifestations. The same was
true when BAL treatment was combined
with intravenous casein hydrolysate and
oral potassium sulfide, the latter forming
an insoluble copper compound in the di
gestive tract (102); and also when EDTA
( ethylenediamine-tetra-acetic acid, or "ver
sene") was extensively tested (46). Nine
weeks of estrogen treatment of an adult
male with Wilson's disease failed to im
prove serum copper or ceruloplasmin
levels (652). Intravenous use of a purified
concentrate of human ceruloplasmin also
proved ineffective (681). These discourag
ing results, together with the adverse side
effects of BAL therapy, stimulated search
for better measures.
In 1956 Walshe (820) described the re
markable effectiveness of oral DL-penicillamine
as a chelating agent capable of mark
edly increasing the urinary output of
copper. A few years later die less toxic
D-penicillamine (ß,/3-dimethylcysteine) be-
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