Antithyroid Drug-Induced Hematopoietic Damage:

A Retrospective Cohort Study of Agranulocytosis and

Pancytopenia Involving 50,385 Patients with Graves
Disease
Natsuko Watanabe, Hiroto Narimatsu, Jaeduk Yoshimura Noh,
Takuhiro Yamaguchi, Kazuhiko Kobayashi, Masahiro Kami, Yo Kunii,
Koji Mukasa, Kunihiko Ito, and Koichi Ito
Ito Hospital (N.W., J.Y.N., Y.K., K.M., Ku.I., Ko.I.), Tokyo 150-8308, Japan; Advanced Molecular
Epidemiology Research Institute (H.N.), Faculty of Medicine, Yamagata University, Yamagata 990-8560,
Japan; Biostatistics (T.Y.), Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan;
Department of Hematology (K.K.), JR Tokyo General Hospital, Tokyo 151-8528, Japan; and Division of
Social Communication System for Advanced Clinical Research (M.K.), the Institute of Medical Science,
the University of Tokyo, Tokyo 108-8639, Japan
Context: Althoughantithyroiddrug(ATD)-inducedhematopoietic damageis asignificant concern,
it has not been comprehensively investigated.
Objective: Our objective was to describe the clinical features of ATD-induced hematopoietic
damage.
Design and Setting: This was a retrospective cohort study in Tokyo, Japan.
Patients: Between January 1983 and December 2002, 50,385 patients at Ito Hospital were diag-
nosed with Graves disease. We retrospectively reviewed their medical, pathological, and labora-
tory records between January 1983 and December 2010.
Main Outcome: Incidence and clinical features of ATD-induced agranulocytosis and pancytopenia
were evaluated.
Results: Of 55patients withdocumentedhematopoietic damage, 50hadagranulocytosis and5had
pancytopenia. All of them received ATD, either methimazole (n 51) or propylthiouracil (n 4).
Median intervals between initiation of ATD therapy and the onset of agranulocytosis and pancy-
topenia were 69 d (range, 11233 d) and 41 d (range, 3297 d), respectively. Either anemia or
thrombocytopenia was also documented in seven of the 50 patients with agranulocytosis. Agran-
ulocytosis was the first manifestation of hematopoietic damage in four of the five patents with
pancytopenia. Hematopoietic damage recovered with supportive measures including granulocyte
colony-stimulating factor (n 37), steroids (n 10), and other supportive measures (n 8) in 54
patients, whereas the remaining patient died of complications frominfection. This study failed to
identify the risk factors for ATD-induced hematopoietic damage.
Conclusions: This study showed that ATD cause hematopoietic changes, which are occasionally
severeandpotentiallyfatal. Thepathogenesis of agranulocytosis andpancytopeniamight overlap,
and additional studies are warranted to clarify this and to establish an optimal treatment strategy.
(J Clin Endocrinol Metab 97: E49E53, 2012)
ISSN Print 0021-972X ISSN Online 1945-7197
Printed in U.S.A.
Copyright 2012 by The Endocrine Society
doi: 10.1210/jc.2011-2221 Received August 3, 2011. Accepted October 11, 2011.
First Published Online November 2, 2011
Abbreviations: ATD, Antithyroid drug; G-CSF, granulocyte colony-stimulating factor; GD,
Graves disease.
J C E M O N L I N E
B r i e f R e p o r t E n d o c r i n e C a r e
J Clin Endocrinol Metab, January 2012, 97(1):E49E53 jcem.endojournals.org E49
A
ntithyroid drugs (ATD) have been used as the stan-
dard therapy for Graves disease (GD) since their
initial development in 1941. These agents, however,
cause various adverse reactions, of which hematopoi-
etic organ toxicity is particularly well known. Use of
methimazole or propylthiouracil causes agranulocyto-
sis in 0.10.5% of treated patients, and some events
become life-threatening (1).
Pancytopenia also occurs in some patients adminis-
teredATD. Its incidence, however, is muchlower thanthat
of agranulocytosis, with only 42 patients reported to date
(213). Eight of those patients died due to hemorrhage or
infection, suggesting that the clinical course of patients
with pancytopenia is more serious than those with agran-
ulocytosis. However, information regarding the clinical
and pathological features of pancytopenia is still insuffi-
cient, and there is no consensus regarding either its diag-
nosis or treatment. Furthermore, although hematopoietic
disorders after administration of ATD are extremely im-
portant complications, to date, there have been almost no
studies that have dealt with agranulocytosis and pancy-
topenia in a comprehensive manner.
Ito Hospital is one of the largest hospitals in Japan
specializing in thyroid diseases. We conducted a retro-
spective cohort study investigating the incidence and clin-
ical features of agranulocytosis and pancytopenia that oc-
curred after administration of ATD in patients with GD
who were treated at Ito Hospital between 1983 and 2002.
Patients and Methods
Study patients
We conducted a retrospective cohort study between January
1983 and December 2002.
Atotal of 50,385patients at ItoHospital were diagnosedwith
GD. We retrospectively reviewed their medical, pathological,
and laboratory records at Ito Hospital and the hospitals where
the patients were transferred between January 1983 and Decem-
ber 2010.
The patients who were newly treated with ATD routinely
underwent blood examinations including complete blood cell
counts once every 2 wk. The patients who developed agranulo-
cytosis or pancytopenia routinely underwent blood examina-
tions every day. These patients were managed in hospitals.
The median age of the patients was 35 yr (range, 1295 yr).
Of them, 9,391(19%) were male and40,992(81%) were female.
Gender information was not available in the remaining two pa-
tients. This study was approvedby the institutional reviewboard
of Ito Hospital.
Management of GD and diagnosis of ATD-induced
agranulocytosis and pancytopenia
Methimazole is usually the first-line therapy for GD at Ito
Hospital, although pregnant women receive propylthiouracil
due to the concerns of fetal teratogenesis or transmission of me-
thimazole through breast milk (14, 15).
Diagnosis of ATD-induced agranulocytosis was made when
patients showed a granulocyte count of less than 500/l after
ATD administration (16). ATD-induced pancytopenia was di-
agnosed when, in addition to agranulocytosis, the patients
showed a hemoglobin concentration of less than 11.0 g/dl and a
platelet count of less than 100 10
9
/liter. We defined resolution
of ATD-induced agranulocytosis or pancytopenia as recovery of
granulocyte counts to 500/l or higher.
Statistical analysis
SAS version 9.1.3 (SAS Institute Inc., Cary, NC) was used for
all statistical analyses.
Results
Incidences of ATD-induced agranulocytosis and
pancytopenia
Diagnoses of ATD-induced agranulocytosis were es-
tablished in 55 patients. Of those, five patients were di-
agnosed as having ATD-induced pancytopenia. The cu-
mulative incidence of ATD-induced agranulocytosis and
pancytopenia at 100 and 150 d after initiation of ATD
were 0.28% (95% confidence interval 0.200.36%)
and 0.29% (95% confidence interval 0.210.37%),
respectively (Fig. 1).
Clinical courses of patients with ATD-induced
agranulocytosis and pancytopenia
The clinical characteristics of the 55 patients with
ATD-induced agranulocytosis and pancytopenia are
shown in Table 1. Median intervals between initiation of
ATD therapy and the onset of agranulocytosis and pan-
FIG. 1. Of the 50,385 patients, 186 patients with GD treated with
ATD who did not develop agranulocytosis or pancytopenia were
randomly extracted to evaluate the incidence of development of
agranulocytosis and pancytopenia. The Kaplan-Meier method was
used to evaluate the incidence of agranulocytosis and pancytopenia in
the patients with GD treated with ATD.
E50 Watanabe et al. Antithyroid Drug-Induced Hematopoietic Disorders J Clin Endocrinol Metab, January 2012, 97(1):E49E53
cytopenia were 69 d (range, 11233 d) and 41 d (range,
3297 d), respectively.
Of the 50 patients with agranulocytosis alone, seven
also showed either a hemoglobin concentration of less
than 11.0 g/dl or a platelet count of less than 100 10
9
/
liter at the onset but not both and, hence, were not labeled
as pancytopenia. Of the five patents with pancytopenia,
development of agranulocytosis preceded the develop-
ment of pancytopenia in four of them. One patient dis-
played thrombocytopenia at the onset of agranulocytosis.
Outcomes of the patients with ATD-induced agranu-
locytosis and pancytopenia are shown in Table 1 and Sup-
plemental Table 1 (published on The Endocrine Societys
Journals Online web site at http://jcem.endojournals.org).
All of the patients with agranulocytosis alone were suc-
cessfully treated with granulocyte colony-stimulating fac-
tor (G-CSF) (n 35), steroids (n 7), or supportive care
alone (n 8). The recovery periods with the different
therapies were 7 d (range, 222 d), 9 d (511 d), and 9 d
(421 d), respectively. Patients treated with G-CSF recov-
ered earlier than those who did not receive it [7 d (222 d)
vs. 9 d (421 d) (P 0.004)].
All of the five patients with pancytopenia developed
febrile episodes, and four of them developed documented
infections including tonsillitis (n4) andpneumonia (n
1). Pancytopenia was initially treated with G-CSF (n 2)
and dexamethasone 46 mg/d (n 3). In four of the pa-
tients, pancytopenia subsided within 14 d of onset of ther-
apy; two patients treated with G-CSF recovered after 9
and 10 d, and two patients treated with dexamethasone
recovered 8 and 10 d after the onset. There were no dif-
ferences in recovery periods between the two therapies.
Pancytopenia was refractory in the remaining patient
treated with dexamethasone (Supplemental Table 1). This
patient developed fatal gastrointestinal hemorrhage and
received2000mgantithymocyte Ig(38.8mg/kg d) for 4d
but died due to pneumonia 102 d after the onset of pan-
cytopenia (Supplemental Fig. 1). Two patients developed
TABLE 1. Characteristics of patients with agranulocytosis and pancytopenia
Variables
Patients with
agranulocytosis
alone
Patients with
pancytopenia P value
No. of patients 50 5
Age (yr) 41 (1274) 48 (3867) 0.12
Sex (male/female) 3/47 0/5 0.57
ATD (methimazole/propylthiouracil) 46/4 5/0 0.51
Interval between initiation of ATD therapy and onset
of agranulocytosis/pancytopenia (d)
69 (11233) 41 (3297) 0.42
Daily dose at onset of agranulocytosis (mg/d)
Methimazole 30 (530) 20 (1060) 0.55
Propylthiouracil 300 (100300) NA
Cumulative dose at onset of agranulocytosis (mg)
Methimazole 954 (2532700) 1568 (12002109) 0.09
Propylthiouracil 9200 (810015000) NA
Laboratory findings at diagnosis of GD
White blood cell count (l
1
) 5200 (32008500) 5900 (37006600) 0.79
Granulocyte count (l
1
) 2600 (16006300) 3100 (24003500) 0.46
Hemoglobin (g/dl) 12.8 (10.114.2) 13.2 (10.614.6) 0.62
Platelet count (10 10
9
/liter) 233 (89339) 201 (188244) 0.43
Total bilirubin (mg/dl) 0.5 (0.32.1) 0.6 (0.40.7) 0.75
Aspartate aminotransferase (IU/liter) 29 (1491) 27 (2643) 0.73
Alanine aminotransferase (IU/liter) 32 (16179) 37 (2571) 0.41
Blood urea nitrogen (mg/dl) 16 (1025) 13 (1018) 0.52
Creatinine (mg/dl) 0.6 (0.31.0) 0.5 (0.40.7) 0.25
Laboratory findings at onset of agranulocytosis/pancytopenia
White blood cell count (l
1
) 1300 (4004500) 900 (2002700)
Granulocyte count (l
1
) 18 (0416) 4 (0108)
Hemoglobin (g/dl) 12.2 (8.514.7) 9.3 (9.111.0)
Platelet count (10 10
9
/liter) 250 (61471) 89 (36100)
Febrile episode (38.0 C) n (%) 46 (92) 5 (100)
Documented infection n (%) 37 (74) 4 (80)
Initial treatment of agranulocytosis/pancytopenia (n)
G-CSF 35 2
Steroids 7 3
Supportive care 8 0
Patient fatalities n (%) 0 1 (20)
Unless indicated otherwise, results are shown as median (range). NA, Not applicable.
J Clin Endocrinol Metab, January 2012, 97(1):E49E53 jcem.endojournals.org E51
transient decreases in neutrophil count after recovery. No
adverse effects of G-CSF or steroids were documented in
any of the 55 patients.
Pathological features
None of the patients with agranulocytosis underwent
bone marrow examination. Two patients with pancyto-
penia underwent bone marrow aspiration at the onset of
pancytopenia. In these patients, bone marrow samples
showed severe hypoplasia, similar to that seen in severe
aplastic anemia. (Supplemental Fig. 2).
Risk factors of ATD-induced agranulocytosis and
pancytopenia
In the probable risk factors of ATD-induced agranulo-
cytosis, no significant factors were selected in the multi-
variate model (Supplemental Methods and Supplemental
Table 2). The characteristics of patients withGDandwith-
out agranulocytosis or pancytopenia are shown in Sup-
plemental Table 3. There were no differences in the oc-
currence of minor adverse effects between the two types of
ATD. In this study, the risk factors of ATD-induced pan-
cytopenia could not be definitively determined (Table 1).
Discussion
This study elucidated the clinical features of hematopoi-
etic disorders that occur after the administration of ATD.
Of the 50,385 patients analyzed in the present study, five
patients developed pancytopenia after treatment for GD.
The data (not shown) as of March 2005 showed that
77.7% of the patients at Ito Hospital who had been diag-
nosed with GD were administered ATD. Using this esti-
mation, the incidence of pancytopenia in our study group
can be estimated to have been approximately 0.01%. In
addition, the incidence of agranulocytosis was approxi-
mately 0.3% in this study (Fig. 1), which is in agreement
with that reported in the published literature (1).
In four of the patients in this study, pancytopenia was
preceded by agranulocytosis. In addition, agranulocytosis
and pancytopenia showed no manifest differences in their
intervals of onset from the start of ATD administration.
These facts indicate the possibility that agranulocytosis
and pancytopenia in these cases could belong to the same
disease entity, there probably being some overlap in their
pathogenesis, and a difference only in their severity. This
would mean that, as has been indicated by earlier basic
research (17, 18), ATD damage hematopoietic stem cells.
The thinking to date has been that an autoimmune mech-
anismthat targets an antigen on neutrophils is involved in
the onset of agranulocytosis due to ATD (19). However,
if that hypothesis were valid, then erythrocytes and plate-
lets wouldremainnormal, whichis contrarytoour present
observations. The pathogenic factors involved in erythro-
poietic organ disorders caused by ATD are diverse and
require further research. Analyses of the pathological find-
ings of bone marrow of a greater number of cases may
prove effective in elucidating these pathogenic factors.
The prognosis of agranulocytosis after treatment has
improved due to advances in supportive therapy, includ-
ing antibiotics, blood transfusions, G-CSF, etc. (20). In
fact, all of the patients included in the present study who
were diagnosed with agranulocytosis were successfully
treated. On the other hand, there are insufficient data re-
garding the treatment results for pancytopenia. Because
one of two patients who developed hematopoietic disor-
ders that were equivalent to severe aplastic anemia died, it
indicates the possibility that the prognosis of severe pan-
cytopenia is poor. GD itself is a benign disease. In clin-
ical practice, because the use of ATD is common, phy-
sicians should be aware that this often-prescribed
therapy for a benigndisease coulditself leadtolife-threat-
ening complications.
Treatment of agranulocytosis with G-CSF seems to
yield good results (1). On the other hand, there is ex-
tremely limited information regarding the treatment of
pancytopenia. Treatments for pancytopenia include sup-
portive therapy using blood transfusions, G-CSF admin-
istration, etc., and immunosuppression centered on
administration of antithymocyte globulin. However, be-
cause the risk of infection with antithymocyte globulin is
high, it must be usedwithgreat care. For patients withmild
pancytopenia, it is probably appropriate to administer
supportive therapy and monitor the clinical course as was
done with three patients with comparatively mild pan-
cytopenia in this study. On the other hand, one of our
patients with severe pancytopenia who received only
supportive therapy also recovered. This indicates that im-
munosuppressive therapy may not be essential even for
severe cases. In this regard, treatment of ATD-induced
pancytopenia differs from treatment of severe aplastic
anemia. Further research is needed to clarify which pa-
tients require immunosuppressive therapy.
In this study, no significant risk factors for the onset of
agranulocytosis after ATD were identified (Supplemental
Table 2); bothmethimazole andpropylthiouracil hadsim-
ilar incidences of development of agranulocytosis. Our
analyses also failed to elucidate any risk factors for pan-
cytopenia, but that was probably inevitable in viewof the
small number of patients who developed pancytopenia in
this study (Table 1). Thus, identification of risk factors for
the onset of hematopoietic damage proved unsuccessful.
This is in agreement with current consensus, because it
is thought that immunological responses that cannot be
E52 Watanabe et al. Antithyroid Drug-Induced Hematopoietic Disorders J Clin Endocrinol Metab, January 2012, 97(1):E49E53
predicted on the basis of other background factors are
involved in the onset of agranulocytosis (1). Other factors
than those that have been investigated to date, such as
genetic predisposition, will probably need to be taken into
consideration for future identification of risk factors for
agranulocytosis.
Unfortunately, our study has a number of limitations.
A major limitation of our study is the fact that it was a
retrospective study. However, prospective clinical studies
are very difficult to carry out in the case of diseases that
occur at a low incidence, such as the hematopoietic dis-
orders caused by ATD. It will be necessary to apply other
investigative techniques, such as creation of an adverse
event database, to obtain more information. Optimal
treatment methods can then be developed on the basis of
those data.
Acknowledgments
We thank Dr. Hiraku Mori (Showa University Fujigaoka Hos-
pital, Tokyo, Japan) for providing us with clinical data and bone
marrow findings.
Address all correspondence and requests for reprints to:
Jaeduk Yoshimura Noh, M.D., Ph.D., Ito Hospital, 4-3-6
Jingumae, Shibuya-ku, Tokyo 150-8308, Japan. E-mail:
h-yoshimura@ito-hospital.jp.
Disclosure Summary: The authors have nothing to disclose.
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