Full text of DOI:10.1177/0148607100024006361

Case
Report
after Removalof
Pancytopenia
fromTotal Parenteral
Copper
Nutrition
M. Patricia
Fuhrman, MS,
RD, CNSD*;
Herrmann, MD, CNSP†;
Virginia
Patricia
and Charles
MD§
Masidonski, RN;‡
Eby,
*Nutrition
Saint Louis
School
of Medicine;
From the
of
Support,
Internal
University
Hematology/Oncology,
Hospital; †Department
Surgery, Washington University
and
of
§Department Pathology,
Saint Louis
of
Medicine,
Saint Louis
‡Department
University;
St
School
Missouri
Louis,
of Medicine,
University
who
cholestatic
dur-
increased serum
and
counts and
ABSTRACT. Patients
develop
nutrition
jaundice
copper, neutrophil
platelet
from
cell
can
red
level reached 186
transfusions. When the serum
was
chronic total
(TPN)
develop sig-
independence
ing
parenteral
due to
A
if
nificant
complications
is withheld.
copper
μg/dL, copper supplementation
hematologic
hypocupremia
level fell
with
Over the next
3
serum
female
discontinued.
months,
copper
36-year-old
copper supplementation
liver
to 10
and red cell
and
counts fell
shortbowel
syndrome
developed progressive
dysfunction
neutrophil
platelet
precipitously,
again,
μg/dL,
transfusions were Once
resumed.
TPN. Trace elements were omitted
months after initiation of
6
copper,
rebounded with
paren-
anemia
TPN
cholestasis
and
levels
from her
because of
and
neutrophil
platelet
promptly
persistent hyperbil-
of some
and
teral
irubinemia.
chronic
diarrhea,
absorption
copper supplementation. Although
neutrope-
Despite
was
from her oral diet. Fifteen
nia are
of
well-recognized hematologic consequences
copper
dietary copper
anticipated
months
the
became red cell transfusion
and
hasbeen
This is
to TPN-related
later,
depen-
reported.
patient
deficiency, thrombocytopeniararely
and her
After 19
serum
counts
the
per
of
declined.
first
report
dent,
neutrophil
platelet
cop-
in which the association was confirmed when
steadily
pancytopenia secondary
Parenteral and
Enteral
of
level
TPN
her
months
without trace
elements,
receiving
deficiency
25
was
70 to 155
was associated with
recurred.
copper
(normal:
of
μg/dL).
hypocupremia
Nutrition
(Journal
2000)
μg/dL
Provision of trace elements for
2
months
24:361-366,
is
added to
nutrition
duodenum to 30 cm of distal ileum. Colonic
Copper
routinely
parenteral
proximal
solutions as
tion after
a
of
a
trace element
was maintained.
she
component
prepara-
continuity
Subsequently,
expe-
of
neutro-
skele-
and
(anemia
rienced
chronic
due to short bowel
chronic TPN. Evaluation for
risk factors for venous throm-
reports
hematologic
malabsorption
in
adults and
penia) complications
and
and
hematologic,
syndrome
congenital
required
acquired
in
and
total
children due to
associated
tal,
neurologic complications
nutrition
(TPN)-
parenteral
copper
boembolisms was notable for
for Factor
homozygosity
because
is excreted
However,
bile,
deficiency.’
copper
advocate
pri-
or
V
Leidenand
The
concurrentuse oforal
elevated
contraceptive pills.
in the
some
experts
marily
reducing
amino-
patient developed
aspartate
in
who
chronic
curtailing copper supplementation
patients
transferase
12
to 50
93
ala-
to 55
nor-
(AST,
U/L; normal,
83
U/L),
chronic
during
hyperbilirubinemia
case a
develop
nine aminotransferase
3
(ALT,
U/L; normal,
is
a
of
with short
TPN.2-4 This
report
patient
and
139
U/L),
mal 10
mild
(GGT,
U/L;
y-glutamyltransferase
and TPN-associated
bowel
binemia
syndrome
hyperbiliru-
pancytope-
in
A
1994. liver
and
Her
needs
to 60
showed
U/L)
July,
biopsy
and
byhypocupremia
complicated
for
TPNwas
X
inflammation,
portal
serologies
Hepatitis
adjusted
nia
a
result of omission of
from the
copper
paren-
as
and
C
were
to
A, B,
negative.
energy
teral nutrition solution.
estimated
with
a
(BEE
1.3),
provide
fuel
Vita-
and
mixed
min
of
amino
acids, dextrose,
lipids,
CASE REPORT
8
months
a
rise in
(5
However,
later,
mg/d).
B12
In
with
a
woman
1994,
January
39-year-old
presented
and
0.2 to 1.3
serum bilirubin to 10.9
(normal,
biopsy,
fibrosis,
mg/dL
and
acute abdominal
pain
peritonitis
which
demon-
and cholestasis
from chronic
a
second liver
mg/dL) prompted
strated mild
Exten-
an
required
emergencyexploratorylaparotomy.
steatosis,
early
sive small
infarction
to
a
a
thrombosed
subtotal small
bowel
secondary
with metabolic
consistent
complications
mesenteric vein necessitated
resection
superior
bowel
TPN.
(ERCP)
obstruction or
Endoscopic retrograde cholangiopancreas
with
anastomosis of 30 cm of
primary
examination demonstrated no
biliary
strictures. Because of concerns that IV
admin-
copper
overload
in
istration could cause
the
that
her
hepatic copper
ofcholestatic
setting
andthe
jaundice
expectation
Charles
School of
Saint
of
at
Correspondence:
Eby, MD,
Medicine,
Pathology,
Department
3635 Vista
some
would be absorbed
dietary
copper
small
through
Louis
St
University
Grand,
Louis,
MO
63110.
trace element
bowel,
remaining
daily
supple-
361
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362
FIG. 1. Effect of
and
on
values after first red
Hematocrit
1). (A)
cell transfusion
copper
deficiency
50%); 1 ,
supplementation
patient’s hematologic
units of
(day
39%
(normal
range,
to
transfusion oftwo
3.5 to 10.5
differential wasnotordered.
serum
red
levels
(normal
70 to 155
WBC,
graph
(B)
cells; inset,
copper
count
range,
p~g/dL).
white
cell count
x
x
(normal
ANC
breaksin
absolute
ANC,
1.7-7.0
(normal
range,
103 /~LL);
neutrophil
range,
103/f.1L);
indicate
WBC
x
400
Platelet
150to
count
Shadedvertical bars indicate
(C)
days
(normal
range,
10~/p.L).
periods
when
1
mgelemental
was added to
TPN.
copper
daily
Downloaded from pen.sagepub.com at CARLETON UNIV on May 4, 2015

363
FIG. 1. Continued
There
ments
1
chromium 10
manganese
~,g,
0.5
treatment with
and
both
followed
vancomycin
gentamicin.
(copper
mg,
for
in
WBC and
a
zinc
were deletedfromtheTPN. was
a
brief
(5
mg), except
mg),
improvement
platelet
thenext 12
her
total TPN
to
decline.
monthsunsuccessful
count
109 to
116),
During
attempts
reduc-
(days
by
steep
to
rehabilitate
smallbowelincluded
Theintervalbetweenredcell transfusions decreased
remaining
tion in
redistribution of macronu-
2 to 3 weeks
clinical
calories,
every
despite rapid
improvement.
a
6-week trial of
of
hormone
Nineteen months after
TPN
trients,
tation,
growth
supplemen-
discontinuing
copper
insertion of
discontinuation
a
a
bone marrow
normocellular
fuels,
1,
provision
and
was
gut-specific
131),
day
supplementation (Fig.
of
was
that showed
a
gastric tube,
TPN,
temporary
biopsy
marrow,
performed
which
and diarrhea.
andher
numbers of
a
and
complicated by dehydration
adequate
megakaryocytes,
Thepatient’s
from 75 to 50
relative
weightdropped
kg,
erythroid hyperplasia (myeloid:erythroid
serum bilirubin remained elevated. Fifteen months
maturation was
3:1).
myeloid
ratio, 1.5:1; normal,
Myeloid
after
tient
the
and some
and
arrested,
discontinuing copper supplementation,
pa-
for
erythroid precursors
with
2
units
transfusion
ofred cells
contained
abnormalvacuoles. Stainableironwas
large,
required
There was no
and abnormal accumulation of iron within
anemia
1).
1,
symptomatic
(Fig.
day
present,
maturing
red cells
nucleated
was not
or
evidence of acute blood
clinical
(sideroblasts)
loss,
laboratory
or
of
folic
or vitamin
identified.
iron,
acid,
deficiency
hemolysis,
as
cause of
and
few
white blood cell
months her
a
Over the next
(WBC)
Copper deficiency, suspected
possible
B
12.
and she
red
cells.
the
and
counts
infusions of
declined,
thrombocytopenia,
steadily
patient’s neutropenia,
platelet
when
and
2
units
was confirmed
serum
of
anemia,
normal,
worsening
copper
required monthly
70
to 155
One hundred
after the
of
endocarditis with
first red
headache
(25
fJ-g/dL)
ceruloplasmin
days
patient’s
¡.Lg/dL;
eight
15 to 60
concentrations
cell
and fever.
a
severe
she
(7.1
normal,
transfusion,
mg/dL;
mg/dL)
complained
A
standard trace
elemental
embo- were obtained
valve
ele-
Bacterial
133).
1, day
(Fig.
systemic
(aortic
1
mentformulation
byechocardiogram
containing mgof
copper
to the TPN. Over the next 6 weeks
lization wasconfirmed
was added
and aortic
scan
vegetation
raphy
blood
insufficiency),
daily
computed tomog-
levels
the
and
rose,
left
(a
and serum
and and
(CT)
cultures
infarction),
copper
patient’s neutropenia
temporoparietal
for
A
Two weeks
she was
Klebsiella
positive
pneumonia
thrombocytopenia improved rapidly.
Enterococcus
source for her bacter-
after
was
faecalis.
biliary
copper supplementation
begun,
emia
The
was
transfused two
based on the
of
units of red cells for
the did not
a
hematocrit of
red cell
suspected
type
pathogens.
did
use
IV
and
cultures of 21%.
Thereafter,
not
illicit
patient
drugs,
patient
124
for
require
her
TPNcentral catheter
The
after removal
showed no transfusion
antibiotic
tip
support
Copper supplementation
days.
was discontinued whenthe
to
growth.
responded rapidly
patient
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364
serum
rose to 186
serum
excess
contributes to TPN-associated
recommendations
patient’s
1,
day
)JLg/dL
copper
(Fig.
hepatic copper
Overthenext
3
concentra-
liver disease is
to reduce or eliminate
174).
tion
months,
copper
unknown; however,
a
nadirof10
from TPN in
were the basis for our deci-
declined,
rapidly
reaching
)JLg/dL (Fig.
patients
copper
concurrent with
and
with
sion to withhold
1,
272),
day
worsening neutropenia,
anemia,
hyperbilirubinemia
TPN.
intake
and
red
from our
copper
necessitating
patient’s
thrombocytopenia,
cell transfusions. After reinstatementof
Recommendations for
from 1.55 to >2.0
coppersupple-
and neutro-
dietary copper
Because of the
range
serum
mentation,
and
concentration,
ubiquitous
copper
counts rebounded.
mg/d.~
of
in the diet
in shell
fish,
phil
platelet
presence
nuts,
copper
and
(highest
the
to
it is
difficult to
decline
cardiac failure due become deficient
copper
thereafter,
extremely
legumes,
grains),
Shortly
patient began
if
intake
is
to
caloric
adequate
steadily, secondary
progressive
regurgitation
to severe mitral
and aortic valve insuffi-
withthe
ofinfants andchildren
maintained,
exception
milk.’ The
after endocarditis and
A
who are
fed cow’s
American
ciency
exclusively
portal hypertension.
for
of Medical Association recommendation
third liver
confirmed marked
parenteral
biopsy
worsening
0.5
to 1.5
andsteatosis. Newcom-
nutrition
of
supplementation
recommended
copperis
mg/d.9
fibrosis, inflammation,
hepatic
included intractable
ascites,
reducing copper
supplementa-
plications
alopathy,
hepatic enceph- Fleming3
in
and
hemor-
(CT
tion
TPN to 0.15
when
Reductionof
a
mg/d
patient
spontaneous intraperitoneal
develops
abdominal
chronic
a
trace
single
rhages.
imaging techniques
hyperbilirubinemia.
Multiple
visceral
and
and elementcanbe
becausetrace elements are
several
scan,
ERCP),
ultrasound,
problematic
a
angiogram,
direct observation
con-
added as
generally
preparation
during exploratory laparotomy
containing
be more
firmed
of recent onset and
of trace elements.
it
may
Therefore,
patency
splenomegaly
clinically
The
4 months feasibleto reduce
copper
and
veins.
died
by
providing
hepatic
portal
patient
supplementation
her TPN
a
trace element
no more than
chronic
after
was restored to
for the second
three times
copper
preparation
a
week when
binemia.l° Factors
a
time.
patient develops
hyperbiliru-
to
contributing
inadequate absorp-
of
in
our
tion
were
intestinal
dietary copper
patient
DISCUSSION
between
resection with reduced
and
absorptive capacity
rapid
A
deficiency and
was con-
timefrom
causal
transit
(transit
to ileocecal valve was
relationship
copper
gastrointestinal
gastric emp-
Rarer condi-
and
3
minutes).
anemia,
neutropenia,
thrombocytopenia
documenting pancytopenia
tying
firmed in this
tions associated with
by
copper deficiency
patient
acquired
and
to
include excessive oral zinc
interferes with
mucosal
(zinc
hematopoietic recovery corresponding
hypocu-
supplementation 11,12
and its correction after addition of
to
of
out of
intestinal
copper
premia
copper
transport
TPNon two
occasions.
intestinal
separate
is an
malabsorption syn-
epithelium),
and chronic
in total
distrib-
renal
the
essential trace
third
failure.14
clinical features of
element,
andis
dromes, 13
Copper
after
I
TPN-
content
iron and
Table
summarizes
zinc,
body
widely
in 14
uted
the
tissues and
contained
our
human
associated
case
throughout
organs, reaching
copper deficiency
published
in the liver.5 All metalloen-
oxidative reductase
All
concentrations
highest
reports, including
patient.
patients
or
TPN
of
because of
zymes
Examples
copper possess
include
activity.
required long-term
congenital
for
of connective tissue
(Cu/Zn
respiration
small bowel
one
disorders,
except
cancer. Anemia
(n
cross-linking
acquired
patient
reduction of
mitochondrial
dis-
with
(n
oxidase),
1),
(lysl
neutropenia
superoxide
esophageal
02-
(cytochrome C oxi-
or both
after an
TPN
were the first
of
(n
8)
mutase),
5),
signs
copper
andoxidation ofiron from ferrous to ferric state
duration of 11 months
dase),
deficiency
receiving
average
1
The
supplementation.
lacking copper
(ceruloplasmin).1
Numerous
roles of
have been variable time to onset of
of
copper
physiologic
copper
hematologic signs
identified from studies of nonhuman mammaIS6 and
inherited states such as Menke’s
most
reflects differences between
likely
deficiency
patients
in terms ofenteral
and
excretion,
absorption,
copper deficiency
hair
Apartial list ofthe functions of total
mel-
of
copper.
kinky
copper
anin
syndrome.~
body storage
in
et
includes
occurred
three cases. Wasa
formation,
hematopoiesis, myelin
Thrombocytopenia
connective tissue
al23
a
womanwith
reported 69-year-old
prolongedpost-
pigment synthesis,
synthesis,
skeletal
and immune function.1,4,5
smallbowelobstruction whose
after 10 months
count
mineralization,
operative
platelet
of
nadired at
increas-
the exact role or
of TPN,
However,
involved
identity
cuproenzymes
82,000/jjLL
to
2
weeks of
in
functions is unknown or
after
of these
ing
221,000/)JLL
parenteral copper.
many
hematopoiesis. A
with
true for
and Willenbucher24 described
short bowel
a
uncertain. This is
Spiegel
patient
especially
of
is also
Crohn’s
cholestasis,
counts
disease,
complete understanding
copper regulation
syndrome,
whose
in the stom- and
can occur
intra-abdominal
platelet
lacking. Absorption apparently
sepsis
125,000/jjLL
ach and
the small
and both
to
after
throughout
droppedto
withholding
copper
intestine,
97,000
cop-
to
active and
involved.5
mechanisms
be
androse to
after
wasadded
passive
may
per
>200,000/)JLL
transport
most
bound to TPN. Our
count fell to
is
Although
patient’s platelet
83,000/f.1L
plasma copper
to
the
the first
of
and
from
intestinal
understood
ceruloplasmin, copper transport
during
period
hypocupremia
1
mucosato liver andothertissues
when her serum
declined
a
second
the
is
27,000/)JbL
copper
poorly
route of
The
estimated to
excretion is
andis
Conditions lead-
excre-
time.
concurrent medical
Despite
primary
copper
biliary
complications,
and
1.2
absolute
preceded
count
WBC,
approximate
obstruction
mg/d.7
neutrophil
(ANC),
platelet
to chronic
nadirs
ing
biliary
parenteral
copper supplementation
impair
copper
tion and
accumulation. Whether andnormalization ofserumcopper. Mild
maypromote
hepatic
thrombocyto-
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365
I
TABLE
of TPN related
Hematologic complications
copper deficiency
not
vacuoles in
and/or
Y,
N, no; NR,
A, myeloid arrest; B,
myeloid
erythroid
C, sideroblasts; D, hypocellular; E,
yes;
reported;
precursors;
F,
G,
hypochromic;
megaloblastoid.
copper deficiency
J.Lg/dL.
hypercellular;
until
70-155
was
from start ofTPN
*Months
ttypical
diagnosed.
reference
range,
in
cytopenias, typically anemia
was also
chronic
a
is
blood
noted
ciency
peripheral
(92,000/tJbL)
copper-deficient
a
penia
and
&dquo;modi-
and
with
renal failure
receiving
neutropenia,
occasionally, thrombocytopenia.
patient
rather
Decreased bone marrow
than
neu-
whose
oral
copper
supplementation.&dqpuoa;ncytopeniarespondedto
production,
fied&dquo;
diet,
of
increased
destruction,
peripheral
erythrocytes,
cause.
andplatelets to bethe
appears
of
on
A
blood
wide
primary
range
morphologic changes
peripheral
has been
trophils,
and bone marrow
the different
smears
Determining
copper dependent enzymes
biopsies
in association with
are described as
Red involved in
further
deficiency.’
hematopoiesis
investiga-
copper
requires
reported
or
or mac-
tion. Before
mentation from the
cells
microcytic, normocytic,15
withholding
diminishingcopper supple-
and
as
TPN in
with
content
when
patients
hemoglobin
hypochro-
parenteral
hyperbilirubinemia, copper
rocytic,8,16
is
concentrations should be
mic.lS,2l
Reticulocyte count,
reported,
variation
due to measured.24 If the serum
level is
copper
erythrocyte
maybe
Some
elevated and
moni-
lOW,15,16,1J
in
is
deficiencies of iron or
but this is not
TPNis withheld or
to
avoid the
necessary
folate,
reduced,
frequent
coexisting
copper
in
Bone marrow
However,
most cases.
are also variable.
ofiatro-
consequences
documented
morphologic
there are two con-
toring
genic
Onthe basis ofour
deficiency.
findings
copper
withthis
monitor serum
experience
a
relative absence of mature
and
wehave
the
and
sistent
findings:
myeloid
patient,
adopted
following
policy:
and
a
stan-
week,
copper
cells
(bands
segmentedneutrophils),
copper quarterly
cytoplas-
provide
in
and
dard
mic vacuoles
of
marrow
trace element
three times
a
erythroid
myeloid
precursors,
of the bone
preparation
6
in
7
8
and
of
the
to serum
in
8,
respectively,
adjusting
levels.
frequency
response
present
in
Table I. Similar
described
findings
cytoplas-
with
acute
in
havebeen
micvacuoles
reported
patients
or
and
which
are involved in
it does not seem
alcohol intoxication
toxicity
chloramphenicol
REFERENCES
The exact mechanism
after
chemotherapy.&dquo;
by
1. Danks DM:
1988
in humans. AnnuRevNutr
8:235,
Copper deficiency
functions
However,
impaired copper-dependent
unknown.
arrest is
myeloid
2.
IN
Shils ME: Parenteral nutrition:
Modern Nutrition in Health
or Cu
dismutase
to be due to Cu/Zn
superoxide
cyto-
M
Lea
and
8th
Shils
Shike
&
(eds).
Olson, JA,
1430-1458
Disease,
ed.,
ME,
chrome oxidase deficiencies.26 In three
the bone
cases,
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