From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
Artificially
Induced
Thyroid
in Sickle
By Charles
W. Seward,
Cell
John
Suppression
Disease
W. Eaton,
and
Hugh
Chaplin,
Jr.
Depression
of thyroid
function
in patients
with
hemoglobin
SS disease
might be expected
to: (1) reduce
tissue
oxygen
consumption,
(2) decrease
ery-
phosphoglycerate,
and p50, showed
no
change.
Furthermore,
musculoskeletal
symptoms
continued
in the
pattern
throcyte
A possible
explanation
for the lack of
any change
in clinical
status
may be
that decreased
cardiac
output,
with attendant
prolonged
circulation
time and
increased
tissue
oxygen
demand
per
red cell per unit time,
oftset
the absolute
decrease
in tissue
oxygen
con-
2, 3-diphosphoglycerate,
characteristic of the euthyroid
(3)
decrease
p50, (4) increase
the average
level
of erythrocyte
oxygenation,
and
(5)
increase
with
emia
in
vivo
associated
and possibly
symptoms.
red
cell
survival
improvement
in
in musculoskeletal
Accordingly,
an-
150-200
mg
sumption.
The
tered three times a day for 143 days to
portunity
to
a 21-yr-old
observations
association
of
6-n-propylthiouracil
were
male
with
adminis-
hemoglobin
disease.
Thyrosuppression
cated by typical
symptoms
priate
changes
in
chemical
parameters.
tologic
follow-up,
measurements
erythrocyte
H
HEMOGLOBIN
by
due to intracellular
modifications
of
vascular
occlusions,
and
tactoid
the red
change
probably
deoxygenation.
tion
hemoglobin-oxygen
the
Division
Washington
Submitted
May
9,
by
Grant
05548
Gi-2992
6X
Charles
W.
Mo.
University,
St.
Medicine,
Center,
Blood,
Louis,
1972;
Louis,
July
for
the
National
Science
Seward,
M.D.
: NIAMD
School
W.
Louis,
Washington
St.
revised
Institute
John
a hematologic
and
disorder
reduced
by deoxygenated
hemolytic
anemia,
to
and
pain.
red
cell
hemoglobin
multifocal
One
of
the
gen-
may
offer
a
rational
therapeutic
Eaton,
Mo.
Diseases
and
the
and
the
Division
Department
of
of
Hematology,
Anthropology,
Wash-
Mo.
the
University
Louis,
is
shape
the intravascular
sickling
by promoting
designed
to provide
a controlled
reduc-
Medicine,
02918
from
suppression.
to
Tissue
of
CA
from
Washington
St.
St.
thyroid
anemia
is an elevation
of intra(DPG)
concentration,12
which
enhances
It is ironic
that,
in sickle
cell disease,
this
Connective
School
Supported
AM
adaptations
dissociation
of
University,
op-
SS disease.
University
ington
formation
cell lead
exacerbates
Measures
to hemoglobin
an
apeutic application
in the clinical
management of hemoglobin
SS disease.
inflammation
dissociation.
adaptive
hemoglobin
with
erythrocyte
associated
erally
salutory
physiologic
erythrocytic
2,3-diphosphoglycerate
hemoglobin-oxygen
of
provided
make
detailed
clinical
of sickle
cell disease
in
results
uggest
that thyrosuppreswithin
the limits
of symptomatic
physiologic
tolerance
has no ther-
S DISEASE
distortion
elasticity
S. These
From
The
sion
and
of red cell mass, 51Cr
survival,
red cell 2,3-di-
characterized
of
indi-
and approphysical
and bioDetailed
hemaincluding
multiple
OMOZYGOUS
approach
SS
was
study
state.
Hugh
University
3,
from
1972;
Arthritis
of
accepted
the
and
Trainee,
Chaplin,
School
Cancer
Metabolic
6,
1972.
Institute,
Diseases,
NIH,
NIH,
and
by
Grant
by
Grant
Foundation.
Medicine
Ph.D.:
July
National
Division
and
Assistant
Jr.,
of
of
Professor
M.D.:
Medicine
Connective
Washington
Professor
and
University
of
Tissue
Anthropology,
of Medicine
Washington
Diseases,
Medical
Center,
Washington
and
University
Preventive
Medical
Mo.
Vol. 40, No. 6 (December),
1972
905
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SEWARD,
906
Since
thyroid
to increase
hormone
could
hematologic
patients
with
shown
of
be accompanied
to
induced
sickle
clinical
55
or
disease.
document
thyroid
disease.
the
We
and
in such
the
are
of
the
physiologic
suppression
DPG
of
effects
and
of thyroid
erythrocyte
Accordingly,
CASE
Clinical
cell
DPG39
suppression
amelioration
chemical
AND CHAPLIN
erythrocyte
that
by reduced
and
of
the
hemoglobin
undertaken
to elevate
we considered
deoxygenation,
abnormalities
accounts
artificially
been
demand,
hemoglobin
detailed
was
has
oxygen
production
decreased
and
hormone
tissue
EATON,
levels,
symptoms
unaware
of
any
hypothyroidism
present
in
investigation
hematologic
effects
of
a patient.
REPORT
Summary
The patient
was a 21-yr-old
black
male
in whom
sickle
cell disease
had
first been
diagnosed
at age 22 mo. Hemoglobin
electrophoresis
revealed
96%
S + A2 hemoglobin
and 4% F hemoglobin.
The patient
had been followed
at the St. Louis
Children’s
Hospital
and in the Washington
University
Clinics
throughout
his life, chiefly
for painful
musculoskeletal
crises
three
to four times yearly
but rarely
requiring
hospitalization.
Over
the preceding
several
years,
typical
ulcerations
had recurred
over
both
medial
malleoli,
always
symptoms
mild
in
responding
and
dysarthria,
his
of the
to
findings
of
general
state
of
study
were
discussed
consent
Physical
health
was
conservative
during
and
the
in detail
to
his
mental
examination
a
revealed
intercostal
The
deep
The
Investigative
tendon
reflexes
17
and
days
of
precordial
The
lungs
were
lift
were
his
the
and
left
clinical
Il/VI
liver
their
research
malleoli.
was
68
a grade
The
purpose
and
and
The
and
spleen
him
with
had
been
and
plan
informed
ward.
mild
frontal
bossing.
thyroid
gland
regular.
systolic
and
developed
He
The
mother,
speech,
medial
pulse
clear.
he
that
murmur
were
was
Cardiac
not
in
the
palpable.
normal.
Plan
Throughout
privileges
rolling
space.
to
lisping
both
The
1969,
weakness.
admission.
and
admission
texture
and intact
over
of normal
consistency.
left
to
patient
slowness,
The skin was of normal
barely
palpable
and
fourth,
left-sided
prior
the
In
thrombosis
minimal
6 mo
with
prior
revealed
management.
cerebrovascular
slowness,
obtained
examination
local
right-sided
mental
usual
written
a
the
20
wk
of
diet
ad
lib.
Multiple
hospitalization,
mass
was
measured
study
was
begun
that
day
to
2 of
date.
the
baseline
prior
on
on
hospitalization
institution
of
hospitalization,
Complete
patient
observations
allowed
full
obtained
during
thyrosuppressive
and
blood
was
were
counts
the
were
ambtatory
medication.
initial
autoerythrocyte
obtained
at
least
the
first
Red
cell
survival
twice
weekly.
Protein
bound
iodine
(PB!),
bilirubin,
cholesterol,
red cell DPG
concentrations,
and p50
(the partial
pressure
of oxygen
at which
50%
of the
hemoglobin
is oxygenated)
were
obtained
every
1-2 wk. Serum
thyroid-stimulating
hormone
(TSH)
and tetraiodothyronirte
(T4) were measured
at 3-4 wk intervals.
Red cell mass
and autoerythrocyte
survival
were
remeasured
after 6 and 12 wk of thyrosuppressive
medication.
The
patient’s
clinical
status
was carefully
reevaluated
at least weekly
throughout
his hospitalization.
6-n-Propylthiouracil,
150
mg
three
times
a day
orally,
was
begun
on the
17th
day
of
hospitalization
increased
Laboratory
and
to 200
mg
continued
three
at
times
that
a day
dosage
for
an
for
additional
74
days.
Thereafter,
the
dose
was
69 days.
Methods
Complete
blood counts, serum
bilirubin, cholesterol,
and
FBI concentrations
were
determined
by routine
methods.
Serum
TSH levels
were measured
as described
by Odell
et al.;10
T4 was
measured
according
to Murphy
and
Jachan.ll
Erythrocyte
2,3-DPG
was
determined
as described
by Keitt,’2
and
p50 was
measured
by the method
of
Lenfant
et al.13
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
THYROID
SUPPRESSION
IN SICKLE
Red cell mass
and red cell
labeled
with 51Cr. Whole
blood
in three
initial
samples
(drawn
cells)
and
the
total
from whole
of the three
hematocrit
CELL DISEASE
907
survival
were
measured
employing
volume
was calculated
employing
20, 40, and 60 mm after
injection
radioactivity
injected.
Red
blood
volume
employing
the
samples,
suitably
corrected
cell
mass
and
the patient’s
red cells
the average
radioactivity
of the 51Cr-labeled
red
plasma
average
of duplicate
for trapped
plasmal4
volume
were
well-oxygenated
and for the
calculated
hematocrits
body/venous
ratio.’5
RESULTS
Clinical
Status
the
During
over
the
area
of
3
medication,
Throughout
with
the
transient
the
and
adequately
week
were
gland
was
were
normal,
was
week,
otherwise
daily,
and
firm,
more
lethargic.
gland
delayed
was two
return,
Although
of
a vascular
fifth
of his
average
doses
easily
and
reflexes
After
pulse
gland
on
remained
the
at
and
arthralgias,
not
was
chiefly
of
and
hydrochloride.
clearly
mg
daily),
mean
(Table
1).
enlarged,
deep
to be two
and
the
thiouracil
the Achilles
forearms
and
beats/mm,
By
the
the patient
to 600
mg
times
patient
PB!
The
tendon
unchanged.
estimated
increased
study.
had
symptoms
was demonstrable,
but
thiouracil
was increased
of
60-68
week
of
the patient
symptomatically
“hanging,”
times
enlarged,
skin over
the
thyrosuppressive
musculoskeletal
but
was
were
wk
4
pain
of propoxyphene
enlargement
The
dose
the thyroid
to three
and the
bone
developed
to a maximum
despite
administration
(450
with
early
thyrosuppression
patient
ulcer
week
by
the
20th
administration,
previous
palpable
the
the
healed,
long
typical
more
Achilles
the
period,
by
subsequently
of thiouracil
consistent
wk later
the
control
enlarging
ulcer
definite
thyroid
unchanged.
2
the
episodes
by
eighth
values
reflexes
and
The
wrists,
thyroid
12th
of
complete
epithelialization
entire
period
of thiouracil
relieved
the
TSH
and
week
malleolus,
days)
(3-5
elbows
By
second
left medial
X 4 cm.
was
dosage,
enlarged
somewhat
the
thyroid
reflexes
showed
marked
shins
was dry and flaky.
there
was
a prolongation
of the precordial
lift and some increase
in intensity
of the systolic
murmur.
The patient’s
weight
had increased
by 1.4 kg with no evidence
of dependent
edema.
The patient
was discharged
from
the clinical
research
unit
in the 20th
week to continue
thiouracil,
600 mg daily,
and to be followed
at 2-wk
intervals
as an outpatient,
with the anticipation
of a final measurement
of red cell
mass
and
autoerythrocyte
he became
increasingly
had two acute episodes
comfort
from
his home,
the
dry and
irregular
was
uncertain
Achilles
the thyroid
thyroid
gland
as
to
1 mo
lethargic
and
of vomiting,
how
thiouracil
later.
When
the
times
enlarged
was striking.
The
premature
ventricular
much
was
of
the
were
essentially
acute
immediately
thyroid
was instituted
at 30 mg daily
for an additional
14 days.
The lethargy
reflexes
However,
3 wk
after
discharge
anorectic,
he slept for prolonged
and complained
of increasing
enlargement.
was three
flaky overall.
Lethargy
beats,
thought
to be
thyrosuppression,
cated
daily
survival
normal
patient
and
pulse
was
examined
firm. The skin
was 68
contractions.
with
symptomatology
discontinued,
for
10
and
within
periods,
neck dis-
and
in
was
occasional
Although
it
was
to
due
whole,
dessi-
days
and increased
to 60 mg
nausea
cleared
within
1 wk;
2
wk.
The
goiter
regressed
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SEWARD,
906
to two
times
cessation
enlarged
by
of thiouracil
Laboratory
1 mo
and
was
nearly
normal
EATON,
size
AND CHAPLIN
by
mo
2
after
administration.
Results
All the
results
are summarized
in Table
1. Mean
values,
and ranges
where
are grouped
in four time periods,
the first three coinciding
with
the intervals
initiated
by 51Cr survival
studies
and the fourth
representing
the final 2 mo of observation
after
discontinuance
of thiouracil.
Individual
TSH
and T4 values
are illustrated
in Fig. 1. Despite
clinical
and chemical
appropriate,
evidence
of
thyroid
suppression,
there
were
no
significant
changes
in any
the routine
hematologic
measurements,
in red cell mass or in red cell survival.
The survival
data are shown
in detail
in Fig. 2 to emphasize
their uniformity
and to confirm
that each represented
a single exponential
function
throughout
Table
1. Laboratory
Period I
Days 1.56
Test
(Normal
Range)
PBI g/100
T4 ig/100
ml (5-11)
TSH tU/mI
Period 2
Days 51-105
Period 3
Days 106-162
4.3 (4)
2.6-4.7
4.4 (2)
3.7-5.6
14.7 (2)
9.1-20.2
4198
1073
3125
19.18 (6)
15.1-20.2
36.70 (6)
2.7 (6)
2.0-3.8
.( 2.0 (3)
< 1-2.4
83 (3)
54-101
4400
1002
3498
7.25
19.08 (5)
16.2-22.6
36.45 (5)
34.5-37.5
34.3-37.9
34.8-36.9
9.6 (17)
7.9-10.5
3.31 (17)
2.98-3.69
17.8 (17)
11.1-22.0
29.2 (18)
27-32
15.6 (17)
1 1.7-25.3
5.81 (17)
9.3 (19)
8.7-10.2
3.12 (19)
2.86-3.49
19.7 (19)
10.3-25.7
26.7 (19)
8.9 (8)
7.5-9.8
3.12 (8)
3.01-3.48
19.3 (8)
11.0-27.2
27.0 (8)
9.4 (3)
8.5-10.5
3.23 (3)
2.95-3.50
20.3 (3)
14.6-26.0
29.1 (3)
25-29
25-29
26-32
14.7 (19)
1 1.2-19.4
5.33 (19)
14.0 (8)
10.2-17.9
5.76 (8)
12.9 (3)
9.4-1 7.3
6.90 (3)
4.15-8.15
3.10-7.10
4.00-7.90
161 (3)
154
(4)
6.70-7.15
144 (2)
6.2 (4)’
5.2-7.Ot
7.8 (2)
7.8-7.9
2.6 (2)
ml (4-8)
(2-8)
2.0-3.2
Total blood volume ml
Red blood cell mass ml
Plasmavolumeml
ABC survival t’/2 days
DPG im/g Hb (10-16)
4250
1044
3206
8.20
19.04 (8)
16.7-20.6
35.88 (8)
p50 mm Hg (25-28.5)
Hemoglobin
g/100
ml (14-18)
Red bood cells X 106/cu
(4.2-5.4)
Reticulocytes/100
RBC
(< 2.0)
Hematocrit
/o (3747)
White
blood
cells
X 103/cu
mm
mm
(5.0-10.0)
Plate!ets X 105/cu mm
(1.50-3.50)
Cholesterol
mg/100 ml
(150-300)
Blllrubln
(<1.5)
Patient’s
Mean value;
tRange
mg/100
weight
number
ml
kg
7.40
143-172
145-160
2.4 (7)
1.4-3.1
54.0 (7)
1.9 (7)
1.4-2.1
55.4 (6)
175 (3)
136-223
2.0 (4)
1.4-3.0
56.9 (3)
50.5-55.0
54.2-56.4
56.8-57.0
of tests in parentheses.
of values for the determinations.
Values
Period 4
Days 163-222
5.5 (3)
5.0-6.4
6.8 (1)
2 (2)
< 2-2.5
-
20.10 (2)
18.6-21.6
35.70 (1)
138-150
3.0 (2)
1.8-4.1
-
of
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THYROID
SUPPRESSION
IN SICKLE
CELL DISEASE
909
Desiccated
Thyroid
PTu
14
80
a
-60
Days
Study Periods
u
I
RC M
51Cr
Fig.
da0’
AES
1044mI
survival
periods
110
14
lO73ml
14
of red
(AES)
to artificially
are shown.
The
4
do 106. lOO2mI
Z4do
the fourth
220
3
of measurements
by 51Cr survival
studies,
of thiouracil
(PTU).
165
2-’I
da57’
T-8.2da
1. Relation
erythrocyte
four
study
55
-I
1
induced
first
three
represents
4000
725da
cell
mass
(ACM)
and
thyrosuppression.
51Cr
As
auto-
in Table
1,
coincide
with intervals
initiated
the final 2 mo after discontinuance
.
T.t’doJ
/
82
A2
71
#{149}3
725
0
2000
A
8
0
0
0
1000
#{149}0
A
0
0
A
0
A
500
A
0
Fig. 2. 51Cr autoerythrocyte
survivals
(AES) for study periods
1-3 shown
in
Table 1 and Fig. 1. Note close agreement and good fit to single exponential
functions
ance
each
throughout
of over
occasion.
900/o
the
of labeled
A
‘5-
200
disappear-
cells
on
4
8
12
0 AY S
16
20
24
28
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910
SEWARD,
destruction
improvement
in erythrocyte
of
over
in any
DPG
90%
of
hematologic
or p50.
the
labeled
parameters,
EATON,
AND CHAPLIN
cells. Consistent
with
the
there were no detectable
lack of
changes
DISCUSSION
Patients
variety
with
of
hemoglobin
homeostatic
55
disease
responses,
and
including
other
changes
severe
anemias
in
red
exhibit
cell
a
metabolism
and an enhancement
of oxygen
delivery
by the red cell.2”#{176}The majority
of
the decrease
in hemoglobin
oxygen
affinity
appears
to be due to an accumulation of DPG within
the red cell.”2
Although
all of the factors
that influence
red cell DPG concentration
in vivo are not known,
it is thought
that DPG
elevations
may be caused
by alkalosis,’7
increased
deoxygenation
of the
hemoglobin,’8
and increased
levels
of thyroid
hormones
(triiodoand tetraiodothyronine).9
has
The right shift of the oxygen
been adequately
documented’23
shift
seen
in
other
forms
of
dissociation
and
anemia.
curve
in hemoglobin
is as great as, or greater
Furthermore,
anemias
of
55 disease
than, the
all
sorts
are
frequently
accompanied
by increases
in metabolic
rate, although
there
may
not be a perceptible
increase
in thyroid
metabolism.24
Unfortunately,
any
elevation
of the metabolic
rate in hemoglobin
SS disease
will increase
tissue
oxygen
demand
and therefore
favor
hemoglobin
desaturation.
In fact, since
these changes
in oxygen
demand
and delivery
progressively
favor hemoglobin
deoxygenation
as anemia
becomes
more
severe,
they
could
be of primary
importance
in the pathogenesis
of certain
forms
of sickle cell crises.
In sickle cell disease,
it would
appear
advantageous
to inhibit
the release
of large amounts
of oxygen
from the circulating
erythrocyte
and, thus, reduce
the amount
of sickling
in vivo.
Several
techniques
for artificially
reducing
both
the amount
of hemoglobin
deoxygenation
and the concentration
of
hemoglobin
that
will
sickle
in vivo
have
been
attempted
in the
past.2#{176} These
therapeutic
measures
have been either
too toxic or of too limited
duration
to be of significant
clinical
value.
In addition,
although
these techniques
may
reduce
oxygen
delivery,
they have little or no effect on oxygen
demand.
Since
elevation
of thyroid
function
both
shifts
the oxygen
dissociation
curve to the right and increases
the basal metabolic
rate,
it appeared
useful
to examine
whether
artificially
induced
depression
of thyroid
metabolism
in
a patient
with hemoglobin
55 disease
would
have
the expected
salubrious
effects
of : (1) decreasing
red cell DPG concentrations,
(2) lowering
p50,
(3)
reducing
tissue
oxygen
consumption,
and (4) increasing
the
average
level
of oxygenation
of the circulating
red cell. All these changes
would be expected
to decrease
the severity
of intracellular
tactoid
formation,
to reduce
the
frequency
of sickling
in vivo,
to improve
erythrocyte
survival,
and to reduce
musculoskeletal
complications.
The administration
of thiouracil
over a period
of 143 days
was associated
with symptoms,
physical
findings,
and biochemical
evidence
of thyroid
suppression
in our patient
with hemoglobin
SS disease.
However,
there was no
accompanying
The
absence
change
of
change
in red
in
cell
p50
DPG
or
DPG
concentration,
concentrations
p50,
or red
cell
is remarkable
survival.
in
the
From www.bloodjournal.org by guest on June 18, 2017. For personal use only.
THYROID
light
SUPPRESSION
of
the
between
IN SICKLE
previously
these
mentioned
parameters
present
results
suggest
disease,
thyroid
status
capacity
of the
circulating
The lack
have resulted
documented
increase
in
tissue
cell
that,
red
demand.
consequently,
on both
it
until
only
effects
red
of the parameters
in cardiac
output,
that
which
A reduction
cells
would
red
has
been
p50)
cell
that
DPG
the
The
hemoglobin
SS
oxygen-delivering
were
measured
may
has been extensively
in cardiac
output
have
an increased
suggested
depends
the
would
time
of
the
a single
was
the present
study
of symptomatic
salubrious
effects
and
the
position
of
red
level
of
of the
pain
when
arrhythmia
the
un-
symptomatic
remains
instance
were
that
the
idiosyncratic.
that thyrosuppression,
tolerance,
has
no
no therapeutic
was
disturbing
and
possibility
in this
oxygen
a rate
similar
to
untoward
effects
of observation,
studied,
to have
average
healed
at
No serious
favors
the view
and
physiologic
appears
of sickle
the
musculoskeletal
cardiac
thyrosuppression
However,
the limits
management
of
ulcer
state.
period
with
patient
accompanied
and
pattern
of the
appeared
concentration
on
red cell.2’8
If this is correct,
then
a
the absence
of any effect
of thyro-
malleolar
euthyroid
end
that
in part
concentration
that
symptoms
goiter.
Since
of
of
the
that
an incidental
in the patient’s
observed
subjective
circumstance
cell.
It
curve.
is noteworthy
changed
and
that
observed
were
relationship
metabolism.4’0’3’
determinant
deoxyhemoglobin
within
the circulating
reduction
in cardiac
output
would
explain
dissociation
Finally,
a close
thyroid
the capillaries
with consequent
increased
opportunity
for deThis effect would
offset the over-all
beneficial
effect of decreases
(and,
suppression
indicated
of
special
a primary
effect
on most
from a reduction
oxygen
DPG
the
911
which
elevations
in
is not
DISEASE
work
and
in hypothyroidism.3234
circulation
time,
and
residence
oxygenation.
in
of
CELL
application
within
detectable
in the
clinical
cell disease.
ACKNOWLEDGMENT
We are grateful
for
performing
to Dr.
the
R. D. Utiger
measurements
of the University
of
TSH
and
T4.
of Pennsylvania
Dr.
David
Kipnis
School
of
sity School
of Medicine
kindly
supplied
valuable
advice
on endocrinological
We also
wish
to thank
Mr.
Jeffrey
Mucha
and
Miss
Linda
Schlesinger
preparation
of this manuscript.
Special
appreciation
is expressed
to the
his
cooperation
and
perseverance
during
the
7 mo
of
this
of Medicine
Washington
Univer-
management.
for
assistance
patient,
in
D.Y.,
for
study.
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1972 40: 905-913
Artificially Induced Thyroid Suppression in Sickle Cell Disease
Charles W. Seward, John W. Eaton and Hugh Chaplin, Jr.
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