From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
LIVER
F.
BJJOHN
EXTRACT
M.D.,
MUELLER,
ECENTLY
REFRACTORY
we have
V. R.
had
MEGALOBLASTIC
R.N.,
HAWKINS,
the opportunity
ANEMIA
W.
RICHARD
AND
to study
a patient
M.D.
VILTER,
with
a macrocytic
anemia
and megaloblastic
bone marrow,
who was refractory
therapy
with vitamin
B,2 and refined
liver extract,
but who responded
This type of macrocytic
anemia
is rare, particularly
in this country.
to parenteral
to folic acid.
Observations
made
between
in this
case
support
extract,
vitamin
of another
factor
the
concept
of a chemical
CASE
L. R.
a 52. year
,
by a private
old
six months’
syncope,
and
mess,
vision
heavy
sclerae
His
chest,
heart
but
there
was
reduced
in the
was
toes.
cent,
prior
alcohol
over
a period
and
no clonus
There
were
no
other
per
cent,
34 per
M.C.H.C.
were
intestinal
x-ray
tract,
marrow
blastic
stages
parenterally
(we
have
Thereafter
reticulocytes
third
Reticulocytosis
bitterly
about
the
not
per
cu.
mm.,
the
From
the
These
investigations
Robert
of vitamin
Gould
Department
was
than
cell
count
Research
B12 and
Foundation,
Lederle
Laboratories,
the
no
in
his
He cooperated
lateral
Position
margins.
hyperactive,
Perception
left.
and
microns,
cu.
mm.
of vibration
sense
was
intact
and
with
after
congested
cent,
per
and
the
successive
hemoglobin
papillae
were
Medicine,
University
from
We
wish
Inc.
for
to thank
the
1117
27
folic
and
Co.,
Merck
acid.
of vitamin
B12
of vitamin
B12).
determined
was
on the
cent.
seemed
every
complaining
smooth
lateral
Inc.
then
given
8
tempo-
Ohio.
Rahway,
Co.,
He was
to be a little
Cincinnati,
Inc.,
and
sternal
erythro-
normoblasts
patient
visible
per
there
of Cincinnati,
Merck
early
examination
did not change.
count
had dropped
to ,,i8o,ooo
to
Although
were
the
gastro-
of the
and
4 micrograms
therapy
hematocrit
days.
biopsy
8 micrograms
only
revealed
lower
polychromatophilic
and
day
and
megaloblastic
administered
Erythrocytes
differential
physician
upper
Gm.
micro-
42.
a normal
A needle
at the
6.8
M.C.H.
private
of the
normal.
hemoglobin
with
by the
macrocytic
responses
small
mm.,
cu.
studies
series
fourth
cu.
12.3
done
were
and
day.
per
3550
barium
anemia
by grants
Inc.
was
he admitted
extremely
normal.
per
analysis
E.C.G.,
By the
of three
aided
of
drows-
change
ill.
were
the
M.C.V.
agglutination
each
of Internal
were
a definite
along
reflexes
,,6lo,ooo
A gastric
reticulocyte
occur.
to 6 Gm.
B12 on each
attacks
but
chronically
reddened
test
ankle
cent,
metamyelocytes
of his tongue,
hemoglobin
of vitamin
9-17-48
a history
There
adequate
noted
margins.
He was placed
on multivitamin
tablets
without
relief.
Neurologic
By 9-2.7-48,
ten days after the initial
dose of vitamin
B12, the erythrocyte
micrograms
complaints.
appeared
and
Romberg
in the erythrocyte
counted
did
Increasing
foods.
been
had
tendon
right
per
Kahn,
maximal
were
soreness
mm.
of pernicious
obtained
deep
count
brucella
Bizarre
(See table
,.)
in the diagnosis
several
solid
subjective
probably
who
the
1.9
blood
cu.
arrest
gave
on exertion,
most
family
on
patient
abnormalities.
white
and
maturation
of development.
were abundant.
We concurred
day.
chest
His
atrophic
erythrocyte
per
other
man
the
reticulocytes
cent,
eating
had
was
The
over
Urinalysis,
of the
revealed
reflexes.
sensory
181,440
achlorhydria.
All
more
revealed:
2.0
a histamine-fast
bone
pathologic
liver
existence
ill-humor.
white
normal.
extremities,
examination
platelets
tongue
were
nor
lower
pale,
but
his
were
of years.
a thin,
the
department
B12. The
of breath
from
illness
out-patient
vitamin
shortness
to cold
and
to our
with
patient
to this
irritability
icteric
abdomen
hematocrit
and
sensitivity
revealed
not
in the
micrograms,
count,
His diet
by extreme
referred
anemia
the
time.
of
was
weakness,
prevented
increased
were
Laboratory
worker
and
examination
His
latter
evidence
favoring
maturation.
REPORT
ofpernicious
at any
manifested
Physical
well.
yard
of progressive
The
intake
personality,
per
tongue.
of diarrhea
a rather
railroad
for the treatment
d..ration
sore
failing
history
former
physician
of about
interrelationship
B12 and folic acid and contribute
necessary
for normal
erythrocyte
New
for
their
Jersey
liberal
and
the
supply
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
iii8
LIVER
rary
subjective
cinnati
EXTRACT
the
improvement
General
Hospital
REFRACTORY
patient
on October
MEGALOBLASTIC
continued
2.,
2948
L.R. ,52wd
for
ANEMIA
on a downhill
further
study
,REFRACTORY
course
and
and
was
admitted
MEGALOBLASTIC
0
Cm
to the
treatment.
ANEMIA
0
85
4
3<
.4
#{176}
80
N!
0p
wt
?z
-
.J
00
I4
N
;,%
#)
I..
w
Oct.
Sept.
FIG.
1.-THE
HEMATOLOGIC
i.-Bone
TABLE
Marrow
Date
Polymorphonuclear
ncutrophile
Metamyelocyte
Myelocyte
C
Myelocyte
B
Myelocyte
A
Myeloblast
lymphocyte
monocyte
Eosinophile
Eosinophilic
myelocyte
Basophile
Basophilic
myclocyte
Plasma
cell
cell
Mcgaloblast
Early
Late
Patient
w:tb
Liver
Nov.
REFRACTORY
Extract
erythroblast
ratio
ANEMIA
Megaloblastic
Anemia
Refractory
10-3-48
Vitamin
After
B12
Dec.
M.EGALOBLASTIC
10-13-48
After
Liver
Extract
10-26-48
After
Acid
Folic
48
37
38.5
57
‘4.5
8.
33.5
2.9.5
2.4
3
8.
2.
3.5
5
0.5
3
I
0
0.5
0
10
12.
0
JO
0
0
0
0.5
0
0.5
I
0.5
0
0
0.5
2.
2.
2.
0.5
‘.5
2.
I
1.5
0
0
0.5
0
0.5
0
0
0
5
0
1.5
2.
0
0
0
0
3
4
0
0
1.5
0
I0
Normoblast
Erythroid
WITH
9-17-48
On
Admission
4
erythroblast
Myeloid:
a
PATIENT
4.5
Clasmatocyte
Primitive
on
A
11.5
Monocyte
Young
Counts
OF
0
Lymphocyte
Young
COURSE
7
13
x8.
‘9.5
20.5
33
14
11.5
45
2.4
46
2.:,
4:3
5:4
5:3
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
J.
On
his
papule
F.
MUELLER,
admission,
the
the
of his
on
margin
examination
was
cent,
hematocrit
tests
were
physical
normal
except
forty-five
minutes.
The
for
were
a total
fatty
not
curve
such
as occurs
Again
there
days
ten
was
unchanged
bility
that
i6,
2948
improvement
was
it had
quently
his
blood
blastic
phase
hour
urine
courtesy
Da
started
occurred
and
reached
striking.
The
counts
have
were
to rise
neurologic
folic
acid
and
of Lederle
and
toward
did
not
the
change
respective
days
contents
The
Therapy
folic
results
acidmg.
the
liver
by
the
10-13-48,
hemoglobin
the
to avoid
30
per cent
but
by
was
bone
mg.
7.5
to
each
units
on the
fifth
marrow
to a normo-
appreciably.
following
the
of folic
were
acid
first
dose
of folic
measured
Micrograms
folic
acid/ml.
.0011
-
-
.0025
-
10-17-48
800
7.5
10-18-48
42.5
e.
6.o
33
10-19-48
750
7.5
5.0
49
the
histamine
range
excreted
stimulation
Specimen
,
,. ,
by normal
acid
Pre-histamine
23
Post-histamine
29
ion
subjects.
in December
Free
excre
32.
3.0
repeated
the
as follows:
-
are within
acid,
through
750
with
liver
CliniSubse-
reverted
750
values
intra-
he was
9-48
analysis
day
when
8-48
excretion
possi-
per cent.
10-19-48
9.4 Gm.
10-
A gastric
the
day.
‘0-’
These
4
patient
of refined
U rine
‘
V
.
cx-
previously.
C
0
but
previous
refined
so that
in order
hemoglobin
three
hours,
Although
acid,
16.9
The
stool
period.
slowly
the
of
and
arrest.
of folic
of
from
units
mm.
point
after
hour
i
B12 injected
comparable
normal.
Laboratories.
m I.
course
a
absorption,
to fall,
Cu.
trial
increased
mm.
and
their
at this
therapeutic
its maximum
signs
therapy
collected
A. L. Franklin
Cu.
mg/Kilo)
on
per
function
fat in twenty-four
30
continued
be roughly
count
per
continued
The
preceding
erythrocyte
cells
1,410,000
given
maturation
blood
on a ten day
response
to
same
next
(
no change
per
Gm.
Liver
submaximal
of vitamin
84o,ooo
the
the
would
samples
of Dr.
was
dose
count
cc. of whole
during
mg.
risen
days
oo
of
of maturation.
two
During
patient
total
A reticulocyte
discharged
given
be necessary
the
the
erythrocytc
revealed
was
amount
a small
neurologic
cent.
done
total
slow
showed
patient
numbered
again
he was
might
the
per
7.9 Gm.
for
The
hemoglobin
mm.,
analysis
revealed
to the
except
ulceration.
cu.
An
weight;
the
findings
1119
bromsulphthalein
aspiration
2948,
,
same
a small
cent.
test
marrow
erythrocytes
exairination
clinically,
so that
extract.
i
marrow
of injected
by dry
VILTER
reticulocytes
,
per
W.
per
mm.
mg.
equivalent
and
the
cu.
tolerance
October
response
extract,
transfusion
On October
cal
reticulocyte
liver
0.4
Bone
On
Bone
muscularly,
in sprue.
is roughly
no
cent
glucose
arrest.
the
cc.
Oral
which
was
per
was
to form
I,o5o,ooo
per
of 16 per cent
acids.
an amount
after
Gm./,oo
fat content
R.
the
down
was
1950
of 8.
AND
essentially
count
bilirubin
maturation
Lederle,
gave
broke
cells
retention
5 Gm.
HAWKINS
later
blood
serum
revealed
tract,
erythrocyte
total
specimen
megaloblastic
The
white
of which
a flat
which
cent,
R.
examination
tongue
unchanged.
i6 per
V.
1948
Combined
revealed:
acid
Total
acid
i8
II
30
DIscussIoN
In
1936,
morphologically
Israels
and
Wilkinson’
to pernicious
described
anemia,
but
a type
lacking
of macrocytic
the
clinical
anemia
manifestations
similar
of
achylia
gastrica,
neural
involvement,
jaundice
and glossitis.
The bone marrow
was
megaloblastic,
but the anemia
responded
poorly
or not at all to the usual parenteral
liver therapy.
The authors
suggested
that “achrestic
anemia”
might
be a suitable
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
I 12.0
LIVER
name
since
they
Clutterbuck
in monkeys
sponded
by clinical
to
felt
that
and
Evans2
failed
to
quite
cytic
EXTRACT
well
et al
from
this
and
pathic
DavidsoniS
refractory
tract.
Nine
and
in 1948
improved
of whole
slowly.
liver
response
only
Twelve
mg.
4. The
offolic
in
of
daily
acid.
‘Wills’
34 other
cases
In
the
an
were
and
inadequate
In
patients
the oral
2.
the
were
refractory
iron,
ascorbic
proteolyzed
therefore
diet,
free
and
normal
of the
responded
administration
acid
lingual
papillac.
the
liver
a papain
liver
cx-
transfusions
8 and
that
digest
a moderate
was
there
shown
to
is still
an-
liver. The remaining
response.
They
These authors
also
were
in
‘idio-
‘
refined
and
in
felt
which
4 cases
liver
hydrochloric
patients,
Girwood9
associated
cases
required
reported
with
preg-
syndrome.
reported
to parenteral
to
to
similar
called
liver,
of the
of
they
acid
response
anemia
sprue
Castle1’
refractory
manifestations
reported.
megaloblastic
or
Watson
1946,
which
of refractory
puerperium
macro-
appeared,
‘
and
which
re1938
responded
reports
Davidson
cases
other unknown
hematinic
principle
in the proteolyzed
were
given
folic acid with
a prompt,
but submaximal
proteolyzed
liver to attain
normal
erythrocyte
values.
nancy,
of tropical
factor’
proteolyzed
authors
but
in
subsequently
a prompt
dose
The
anemia
followed
Numerous
2.5
received
with
‘
later
1943,
was
of cases
but
term
All
‘ ‘
patients
Evans4
Wills,
1937,
as Anahaemin
This
liver.
in addition,
orally,
remaining
0.4
the
a total
anemia.
received
and
crude
In
macrocytic
such
Anahaemin,
that
in
described
administered
in the
contain
cases
properly.
induced
extracts
Wills
countries.57
and Innes8
megaloblastic
of these
utilized
as Campolon.
to
factor
experience
followed
from other
In England,
Davidson,
Davis
1946
and
.
work
active
liver
such
to respond
not
ANEMIA
experimentally
to refined
extracts
failed
unknown
was
that
respond
It was
an
MEGALOBLASTIC
extract
by Napier3
which
Campolon.
designate
liver
reported
to crude
reports
anemia
REFRACTORY
of “nutritional
therapy.
anemia
in
the
patients
gastric
Bone
anemia”
had
contents,
marrow
occurred
to liquid
extract
of liver
of a suspension-solution
macrocytic
These
in common
absent
morphology
during
neural
was
pregnancy.
The
not
first
2.
(Valentine).
The third
responded
to
of powdered
liver extract
(Lilly)
and the fourth
responded
to the daily
intravenous
injection
of io cc. of the supernatent
of this ‘special
liver preparation.”
The fourth
patient
received
1.3
mg. of
“L. casei factor”
daily
for io days along
with
other
members
of the vitamin
B
complex
without
benefit
prior to the administration
concluded
that
the crude
liver preparations
given
hematopoietic
factor
not present
in the more refined
of liver extract.
in large
doses
liver extracts.
lingto designate this substance the “Wills’ factor,” and
folic acid.
Waldenstr#{246}m’2in 1947
reported
4 cases
of refractory
which
responded
viously
to liver
to folic
acid
Recently
to folic
and
was
Bethel!
then
classed
and
acid
had
given
become
of these
refractory.
The
one case
steatorrhea.
reported
briefly
believe
macrocytic
Two
as idiopathic
mother
This
not
by mouth.
co-workers’3
cytic anemia
in a 19 year old
the gastric
juice, and glossitis.
did
These authors
contained
some
They were wil-
a case
who had a megaloblastic
anemia
did not respond
anemia,
had
that
that
responded
did
not
of puerpera!
marrow,
to a total
it was
3 of
prerespond
macro-
free acid in
of io gamma
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
J.
F.
MUELLER,
of B,2 intramuscularly
by mouth
The
per
described
of the
other
neurologic
eral
glossitis
failure
and
had
been
no
acid
It seems
acid
acid
range
a mechanism
tioned
by
Studies
which
may
lack
of “intrinsic
the
to purine
nists
on
circumvent
poietic
pyrimidine
growth
effect
of
large
nutritional
be applicable
has
amounts
to the
factors
one
of
from
suggest
possibility
that
The
anemia
before.’9
liver,
vitamin
of
these
factors
and
that
B,2 for
given
folic
a closely
in
large
may
from
acid
amino
and
related
doses,
the
one.
could
in
one
acid
of the
unknown
Under
overcome
are
antago-
The
or
hematopernicious
concepts
points
may
of break-
to convert
thymine
chain
reactions
chemical
acids
and
intimately
human
these
failure
that
thymine
are
to overcome
that
be the
It is likely
to
also.
thymine,
in
B12, condi-
of folic
interrelationships
suggests
acid
action”
in pernicious
pyrimidines
and sprue
of nucleo-protein
and
acid’5
factors
inhibition
present
folic
action
folic
and
of erythbe
of vitamin
these
The
existence
a “mass
link
of purines
the
is true,
that
a pyrimidine,
in pernicious
step
gastric
these
anemia
suggested
formation
derived
one
juice.
ability
nutrition.’8
been
the
metabolism.
the
macrocytic
of hematopoiesis
probably
was
in the
process
by
folic
a defect
it must
factor
hematopoietic
demonstrate
to human
to thymidine
leading
and
of this
for
injection
assume
but
deperni-
deficiency.
role
in the
If this
its
and
of
factor
and
reason,
acid
liver.
‘Wills’
parenteral
is unknown
of bacteria
synthesis
‘
must
folic
deficiency,
in
re-
effect
chemical
same
one
with
explain
requirements
the inhibition’7
anemia,
down
and
bacterial
also
factor”
growth
this
a deficiency
a chemical
when
extract
etiologic
after
For
as proteolyzed
overcome
B,21#{176}
to thymidine
related
any
can
substance
factor
normal
‘liver
‘
ofinfancy
fundamental
Therefore,
of this
such
it overcomes
on
vitamin
identity
was
anemia,
a primary
in conjunction
treatThere
hematopoietic
anemia
persons.
untenable.
after
or steatorrhea.
The
achrestic
same
of this
with
How-
clinics.
demonstrate
is unlikely.
acts
doses
to the
to
patients
acid
as
an
but
Spies.’4
an etiology
tract
European
to have
all due
and
be classified
ofmegaloblastic
excretion
system
must
had
extract,
several
hydrochloric
causes.
by
said
to
periph-
also
liver
Minnich
gastro-enteric
he
in normal
The
his
of mild
similar
such
from
Objective
‘ ‘
patient
of diarrhea
to unknown
fails
preparations
where
due
are
case
which
large
anemia
acid
respects
anemia.
refined
of free
evidence
instances
the
jugase
liver
effect,
of folic
clinical
B,2 and
makes
return
and
persons
expected
maturation.
relatively
io mg.
The
Vilter,
extract
the
reported
many
in our
con
in crude
for
that
factor,
rocyte
‘
to results
because
of another
liver
elimination
anemia’
and
deficiency
folic
112.1
manifestations
was
Moore,
without
By
minor
alcohol.
vitamin
he
by
by
of pregnancy,
the
to
macrocytic
by
respects
surgery
barium.
evidence
within
these
unlikely
probable
anemia
The
VILTER
responded
probably
by
reported
gastro-enteric
anemia”
cious
unrelieved
In
seems
is similar
ficiency
W.
in certain
were
to purified
macrocytic
folic
R.
refractory
induced
is eliminated
with
fractory
was
acid.
sprue
visualized
which
deficiency
anemia
ment,
but
differs
extract
atrophy
to respond
Pernicious
AND
period,
report
present
which
factor
ever,
HAWKINS
day
‘liver
‘
cerebral
to folic
extrinsic
of
were
and
responded
a ten
in our
cases
signs
neuritis
acute
over
R.
day.
patient
most
V.
catalyzed
factor
such
by
are
these
essential
circumstances
temporarily
defi-
From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
I 12.1
LIVER
ciencies
effective
folic
EXTRACT
of the others,
in very large
acid
and thymine,
doses.
Such
in the patient
problems
which
REFRACTORY
arisen
in this
in the
I
.
The
patient
described
arrest
bration
extract
perception
or vitamin
bone
helps
reaction,
would
for the effect
to explain
many
be
of
puzzling
anemias.
CONCLUSIONS
report
marrow,
and
of macrocytic
AND
in this
in the
report
field
SUMMARY
maturation
ANEMIA
one of the substrates
of the
a theory
offers an explanation
described
have
MEGALOBLASTIC
had
macrocytic
glossitis,
anemia,
hyper-reflexia
in the feet. None of these abnormalities
B,2 but all responded
rapidly
to folic
megaloblastic
and
diminished
vi-
was improved
by liver
acid except
the neurologic
signs.
2..
scribed
This patient
appears
to have
in European
clinics
under
megaloblastic
mia”
anemia.
and
This
.
It appears
‘ ‘
of this
substance
an unknown
factor
It seems
likely
action”
effect.
The
liver
anemia
which
has been deanemia’
and
refractory
‘
to
‘
‘Wills’
‘
in the
urine
was
within
extract
to nucleo-protein
deficiency
ane-
acid
the
of folic
normal
synthesis
‘
factor
anemia
of pregnancy.
to have a primary
deficiency
probably
equivalent
to “the
Wills’
that folic acid induced
a remission
possible
relationship
of folic acid,
.
and
a megaloblastic
names
‘achrestic
to be similar
some cases of pernicious
patient
did not appear
excretion
factor
had
the
limits.
factor”
since
A deficiency
of
is suggested.
in this case by a “mass
vitamin
B,2, the unknown
is discussed.
ADDENDUM
Since
the
completion
of this
paper,
the
patient
herein
reported,
has
been
read-
mitted
in hematologic
relapse.
He had received
no interim
treatment
due to his
failure
to report
back to us. During
his second
stay
in the hospital
he was
treated
with
thymine,
13.2.
Gm. daily for ten days. Reticulocytosis
of io per cent occurred
and a rise in erythrocytes
is consistent
with
the
and
theory
hemoglobin
outlined
is in progress.
above.
This
hematologic
response
ACKNOWLEDGMENT
We
in this
wish
to thank
Doctor
Charles
Foertmeyer
for
referring
this
patient
to us for
the
clinical
study
used
report.
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From www.bloodjournal.org by guest on June 17, 2017. For personal use only.
1949 4: 1117-1123
LIVER EXTRACT REFRACTORY MEGALOBLASTIC ANEMIA
JOHN F. MUELLER, V. R. HAWKINS and RICHARD W. VILTER
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