Analysis of 754 cases of antithyroid drug-induced agranulocytosis over 30 years in Japan.
BACKGROUND
Agranulocytosis is a rare but serious complication of antithyroid drug (ATD) therapy. Characteristics of agranulocytosis have been reported in only a small number of patients.


METHODS
We studied 754 cases of ATD-induced agranulocytosis reported over 30 years. The age distribution and sex ratio were compared with those in 12 503 untreated Graves' patients at Kuma Hospital. The annual number of new Graves' patients in Japan was estimated from the Japan Medical Data Center Data Mart-Pharmacovigilance health insurance receipt database.


RESULTS
Agranulocytosis developed within 90 days after starting ATD therapy in most patients (84.5%). The methimazole dose given at onset was 25.2 ± 12.8 mg/d (mean ± SD). The mean age was 43.4 ± 15.2 years, and the male to female ratio was 1:6.3. When compared with patients at Kuma Hospital, patients with agranulocytosis were older (P < .001) and more females (P < .0001). Of 211 patients with more than 1 granulocyte measurement before onset, 131 (62%) showed normal counts (>1000/μL) within 2 weeks before onset, demonstrating real sudden onset of agranulocytosis. In contrast, some of the 20 patients with more than 4 measurements showed gradual decreases in granulocyte counts. Analysis of physician reports for 30 fatal cases revealed that some deaths might have been prevented. The number of new Graves' patients treated with ATD was estimated at about 35 000 per year, and the incidence rate of agranulocytosis was 0.1% to 0.15% in Japan.


CONCLUSIONS
This is the largest study of agranulocytosis. Agranulocytosis tends to occur abruptly within 3 months after initiation of ATD therapy, although it develops gradually in some patients. Providing every patient with sufficient information on agranulocytosis is critical.
Kuma Hospital, Shimoyamate-dori, Chuo-ku, Kobe 650-0011, Japan. hirotosh@kuma-h.or.jp.
Hirotoshi
H
Nakamura
Akira
A
Miyauchi
Natsuko
N
Miyawaki
Junichi
J
Imagawa
D000328:Adult; D016907:Adverse Drug Reaction Reporting Systems; D000380:Agranulocytosis / Q000097:blood / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology; D000741:Anemia, Aplastic / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology / Q000276:immunology; D013956:Antithyroid Agents / Q000009:adverse effects* / Q000627:therapeutic use; D004359:Drug Therapy, Combination / Q000009:adverse effects; D005260:Female; D006111:Graves Disease / Q000097:blood / Q000188:drug therapy / Q000276:immunology; D006786:Hospitals, Urban; D006801:Humans; D015994:Incidence; D007564:Japan / Q000453:epidemiology; D019891:Leukopoiesis / Q000187:drug effects*; D008297:Male; D008713:Methimazole / Q000009:adverse effects / Q000627:therapeutic use; D008875:Middle Aged; D010198:Pancytopenia / Q000097:blood / Q000139:chemically induced / Q000453:epidemiology / Q000276:immunology; D060735:Pharmacovigilance; D011441:Propylthiouracil / Q000009:adverse effects / Q000627:therapeutic use; D017678:Sex Distribution
D013956:Antithyroid Agents; D008713:Methimazole; D011441:Propylthiouracil