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Watanabe et al.
ntithyroid drugs (ATD) have been used as the standard therapy for Graves disease (GD) since their
initial development in 1941. These agents, however,
cause various adverse reactions, of which hematopoietic organ toxicity is particularly well known. Use of
methimazole or propylthiouracil causes agranulocytosis in 0.1 0.5% of treated patients, and some events
become life-threatening (1).
Pancytopenia also occurs in some patients administered ATD. Its incidence, however, is much lower than that
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 agranulocytosis. However, information regarding the clinical
and pathological features of pancytopenia is still insufficient, and there is no consensus regarding either its diagnosis or treatment. Furthermore, although hematopoietic
disorders after administration of ATD are extremely important complications, to date, there have been almost no
studies that have dealt with agranulocytosis and pancytopenia in a comprehensive manner.
Ito Hospital is one of the largest hospitals in Japan
specializing in thyroid diseases. We conducted a retrospective cohort study investigating the incidence and clinical features of agranulocytosis and pancytopenia that occurred after administration of ATD in patients with GD
who were treated at Ito Hospital between 1983 and 2002.
due to the concerns of fetal teratogenesis or transmission of methimazole 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 diagnosed 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 100 109/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.
Study patients
We conducted a retrospective cohort study between January
1983 and December 2002.
A total of 50,385 patients at Ito Hospital were diagnosed with
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 December 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 agranulocytosis or pancytopenia routinely underwent blood examinations 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 and 40,992 (81%) were female.
Gender information was not available in the remaining two patients. This study was approved by the institutional review board
of Ito Hospital.
Results
Incidences of ATD-induced agranulocytosis and
pancytopenia
Diagnoses of ATD-induced agranulocytosis were established in 55 patients. Of those, five patients were diagnosed as having ATD-induced pancytopenia. The cumulative incidence of ATD-induced agranulocytosis and
pancytopenia at 100 and 150 d after initiation of ATD
were 0.28% (95% confidence interval 0.20 0.36%)
and 0.29% (95% confidence interval 0.21 0.37%),
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-
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TABLE 1.
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Variables
No. of patients
Age (yr)
Sex (male/female)
ATD (methimazole/propylthiouracil)
Interval between initiation of ATD therapy and onset
of agranulocytosis/pancytopenia (d)
Daily dose at onset of agranulocytosis (mg/d)
Methimazole
Propylthiouracil
Cumulative dose at onset of agranulocytosis (mg)
Methimazole
Propylthiouracil
Laboratory findings at diagnosis of GD
White blood cell count (l1)
Granulocyte count (l1)
Hemoglobin (g/dl)
Platelet count (10 109/liter)
Total bilirubin (mg/dl)
Aspartate aminotransferase (IU/liter)
Alanine aminotransferase (IU/liter)
Blood urea nitrogen (mg/dl)
Creatinine (mg/dl)
Laboratory findings at onset of agranulocytosis/pancytopenia
White blood cell count (l1)
Granulocyte count (l1)
Hemoglobin (g/dl)
Platelet count (10 109/liter)
Febrile episode (38.0 C) n (%)
Documented infection n (%)
Initial treatment of agranulocytosis/pancytopenia (n)
G-CSF
Steroids
Supportive care
Patient fatalities n (%)
Patients with
agranulocytosis
alone
50
41 (1274)
3/47
46/4
69 (11233)
Patients with
pancytopenia
5
48 (38 67)
0/5
5/0
41 (3297)
30 (530)
300 (100 300)
20 (10 60)
NA
P value
0.12
0.57
0.51
0.42
0.55
954 (2532700)
9200 (8100 15000)
0.09
0.79
0.46
0.62
0.43
0.75
0.73
0.41
0.52
0.25
35
7
8
0
2
3
0
1 (20)
Unless indicated otherwise, results are shown as median (range). NA, Not applicable.
(4 21 d), respectively. Patients treated with G-CSF recovered earlier than those who did not receive it [7 d (222 d)
vs. 9 d (4 21 d) (P 0.004)].
All of the five patients with pancytopenia developed
febrile episodes, and four of them developed documented
infections including tonsillitis (n 4) and pneumonia (n
1). Pancytopenia was initially treated with G-CSF (n 2)
and dexamethasone 4 6 mg/d (n 3). In four of the patients, pancytopenia subsided within 14 d of onset of therapy; 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 differences 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
received 2000 mg antithymocyte Ig (38.8 mg/kg d) for 4 d
but died due to pneumonia 102 d after the onset of pancytopenia (Supplemental Fig. 1). Two patients developed
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Watanabe et al.
Discussion
This study elucidated the clinical features of hematopoietic 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 diagnosed with GD were administered ATD. Using this estimation, the incidence of pancytopenia in our study group
can be estimated to have been approximately 0.01%. In
addition, the incidence of agranulocytosis was approximately 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 mechanism that 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-
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7.
8.
9.
10.
11.
12.
Acknowledgments
We thank Dr. Hiraku Mori (Showa University Fujigaoka Hospital, 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.
13.
14.
15.
16.
References
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2. Biswas N, Ahn YH, Goldman JM, Schwartz JM 1991 Aplastic anemia associated with antithyroid drugs. Am J Med Sci 301:190 194
3. Escobar-Morreale HF, Bravo P, Garca-Robles R, Garca-Larana J,
de la Calle H, Sancho JM 1997 Methimazole-induced severe aplastic
anemia: unsuccessful treatment with recombinant human granulocyte-monocyte colony-stimulating factor. Thyroid 7:6770
4. Jakucs J, Pocsay G 2006 Successful treatment of methimazole-induced severe aplastic anemia with recombinant human granulocyte
colony-stimulating factor and high-dosage steroids. J Endocrinol
Invest 29:74 77
5. Levine B, Rosenberg DV 1954 Aplastic anemia during the treatment
of hyperthyroidism with tapazole. Ann Intern Med 41:844 848
6. Lopez-Karpovitch X, Ulloa-Aguirre A, von Eiff C, Hurtado-Monroy R, Alanis A 1992 Treatment of methimazole-induced severe
aplastic anemia with recombinant human granulocyte-monocyte
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