Thyrotoxicosis is a common endocrine disorder. Antithyroid drug therapy is the standard treatment for this disease, especially in young women of reproductive age. A serious side effect of antithyroid drug use, however, is agranulocytosis. We report on two patients with antithyroid drug-induced agranulocytosis. Both patients presented with fever and severe neutropenia. The administration of granulocyte colony-stimulating factor resulted in a dramatic improvement in the white blood cell count and symptoms. Antithyroid drug-induced agranulocytosis is a potentially lethal condition but is completely reversible when recognised early and when prompt treatment is offered.published_or_final_versio

Lee, CH

Liang, RHS

Hong Kong Medical Journal

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Title Antithyroid drug-induced agranulocytosisAuthor(s) Lee, CH; Liang, RHSCitation Hong Kong Medical Journal, 1999, v. 5 n. 4, p. 394-396Issued Date 1999URL http://hdl.handle.net/10722/162359Rights Creative Commons: Attribution 3.0 Hong Kong License394      HKMJ Vol 5 No 4 December 1999Lee et alIntroductionThyrotoxicosis is a common endocrine disorder. Itaffects mainly women of child-bearing age (prevalence,approximately 2%)1 and is approximately five timesmore common in females than in males. Patientsare usually treated with antithyroid drugs, the mostcommon of which is carbimazole. Antithyroid drugtherapy, however, is associated with a potentially fatalcomplication—namely, agranulocytosis. The incidenceof this particular side effect has been reported torange from 0.3% to 0.6%.2 Although antithyroid drug–induced agranulocytosis is rare, it has been associatedwith a mortality rate of 21.5%.3 We report on twothyrotoxic patients who presented with fever afterhaving taken antithyroid drugs.Case reportsCase 1A 36-year-old woman with thyrotoxicosis presentedto the Queen Mary Hospital (QMH) in November 1994with a fever (temperature, 38.5°C) and a sore throatafter having taken carbimazole 10 mg three times dailyfor 1 month. The white blood cell count at the time ofthe patient’s hospital admission was 0.6x109 /L (normalrange, 3.2-9.8 x 109 /L) and the neutrophil count was0.03x109 /L. Intravenous imipenem was given with onedose of granulocyte colony-stimulating factor (GCSF)Department of Medicine, The University of Hong Kong, QueenMary Hospital, Pokfulam, Hong KongCH Lee, MB, BS, MRCPRHS Liang, MD, FRCPCorrespondence to: Dr RHS LiangAntithyroid drug—induced agranulocytosisCH Lee, RHS LiangThyrotoxicosis is a common endocrine disorder. Antithyroid drug therapy is the standard treatment forthis disease, especially in young women of reproductive age. A serious side effect of antithyroid drug use,however, is agranulocytosis. We report on two patients with antithyroid drug–induced agranulocytosis.Both patients presented with fever and severe neutropenia. The administration of granulocyte colony-stimulating factor resulted in a dramatic improvement in the white blood cell count and symptoms.Antithyroid drug–induced agranulocytosis is a potentially lethal condition but is completely reversiblewhen recognised early and when prompt treatment is offered.HKMJ 1999;5:394-6Key words: Agranulocytosis; Antithyroid agents; Granulocyte colony-stimulating factor300 µg subcutaneously on the day of admission. Thepatient’s white blood cell count increased to 1.6x109 /L(neutrophils, 0) on day 2 and her temperature increasedto 40°C. During the next few days, the white bloodcell and neutrophil counts increased gradually. Onday 4 of hospital admission, the white blood cell countwas 4.4x109 /L (neutrophils, 0.68x109 /L) and thepatient became afebrile. She was discharged home onday 7 with white blood cell and neutrophil countsof 4.1x109 /L and 0.80x109 /L, respectively, and sheremained afebrile. Tests for micro-organisms gavenegative results.Case 2A 40-year-old woman presented to the Accident andEmergency Department of the QMH in May 1998 witha fever. Thyrotoxicosis had been diagnosed 3 monthspreviously, for which the patient had started a courseof a propylthiouracil, but changed to carbimazoleafter 2 weeks because of gastro-intestinal disturbance.On this occasion, she was discharged home and wasgiven oral antibiotics. She was subsequently admittedto the QMH because of persistent fever, and chest andurinary symptoms. The patient’s white blood cell countat the time of hospital admission was 0.44x109 /L(neutrophils, 0) and her temperature was 39°C. Bonemarrow examination showed normocellular marrowand a selective suppression of myelopoiesis. Thesesymptoms were clinically compatible with a diagno-sis of antithyroid drug–induced agranulocytosis. Thepatient was given GCSF 300 µg twice daily, followedby subcutaneous GCSF 300 µg/d and intravenousceftazidime and amikacin. Oral itraconazole was alsogiven on day 2 because of persistent fever. The whiteblood cell count increased gradually to 1.7x109 /LHKMJ Vol 5 No 4 December 1999      395Drug-induced agranulocytosis(neutrophils, 0.45x109/ L) on day 3 of hospital admis-sion and eventually increased to 11.8x109 /L (neutro-phils, 9.80x109 /L) on day 4, when GCSF treatmentwas discontinued. The patient became afebrile and testsfor micro-organisms gave negative results.DiscussionThe two patients described in this report presentedwith antithyroid drug–induced agranulocytosis. Thisis a very rare complication of the use of a commonlyprescribed drug. Antithyroid drug–induced agranulo-cytosis is diagnosed when there is a compatibleclinical history, an absolute neutrophil count of0.5x109 /L or less, and bone marrow histologicalfeatures consistent with agranulocytosis.4 The diagno-sis is not applicable to patients who have neutro-penia due to chemotherapy, or patients with chronicneutropenia, including congenital and chronic auto-immune neutropenia.The immune-mediated destruction of matureneutrophils was the first mechanism to be identifiedas a cause of antithyroid drug–induced agranulo-cytosis.4 Sprikkelman et al4 have described fourdifferent immunological mechanisms that may beresponsible. Firstly, antibodies may develop againstthe antithyroid drug when it is bound to the cell mem-brane of the granulocyte, resulting in an accelerateddestruction of the granulocyte. Secondly, antibodiesmay target the drug/metabolite complex that has beenadsorbed to the neutrophil granulocyte in the presenceof plasma component. Thirdly, the drug may triggerthe production of auto-antibodies. Finally, the inter-action of a granulocyte antigen and drug may inducethe production of antibodies. Besides these mecha-nisms, idiosyncratic drug-induced agranulocytosis,which is a severe selective depression of myelopoiesisdue to an unpredictable adverse reaction to a widevariety of drugs in hypersensitive individuals, has alsobeen a postulated mechanism for agranulocytosis, as wasdocumented for the second patient of this case report.Drug-induced agranulocytosis usually occurswithin 1 to 2 months of taking the antithyroid drug,but the onset of the disease can also be delayed, aswas the case for the second patient. It has beenreported that the white blood cell count usually spon-taneously returns to normal over a period of 1 to 2weeks after discontinuing treatment with the offend-ing drug; the time taken ranges from 7 to 56 days.1,5The speed of neutrophil recovery depends on thenumber of myeloid precursor cells that are present inthe bone marrow. Recovery may be prolonged if thereis granulocyte precursor aplasia. Previous reports havesuggested that giving GCSF can hasten the marrowrecovery to approximately 1 week.1,5 This suggestionwas confirmed in the two patients presented here; bothpatients’ white blood cell count returned to within thenormal range by day 4 of GCSF treatment. At theQMH, treatment is arbitrarily discontinued when theabsolute neutrophil count is  1.0x109 /L or higher, sincethe optimal duration of GCSF therapy for agranulo-cytosis is currently unknown. Only a single dose ofGCSF was used in the first patient. In contrast, GCSFtreatment was stopped when the neutrophil countwas higher than 0.5x109 /L in the second patient. Theinitial dose of GCSF used in the second patient wasdouble that used in the first patient. The usual recom-mended dosage of GCSF is 5 µg·kg-1·d-1, although thereis no large randomised controlled trial that compareseffects of giving other dosages.Agranulocytosis had a poor prognosis in the past,with a reported mortality rate of 21.5%.3 The mortalityrate has decreased significantly in the past two decadesbecause of the availability of potent antibiotics. Theprognosis depends on a variety of factors, such asage, co-morbidity, immediate antibiotic treatment, andduration of severe granulocytopenia. Successful treat-ment of antithyroid drug–induced agranulocytosis byGCSF has been reported in the literature.1,6 A mortal-ity rate of 5% has been reported for 58 patients withsevere agranulocytosis who were treated with GCSF.4These data indicate that GCSF enhances the recoveryof the peripheral blood granulocytic lineage, whichresults in a faster normalisation of the peripheralblood granulocyte count, as well as a reduced inci-dence of fatal complications. This treatment has beenrecommended for most circumstances, and GCSF hasbeen purified, molecularly cloned, and expressed asa recombinant protein.7 It is a potent stimulus fornormal neutrophil proliferation and maturation in vitroand in vivo. Other approved indications includeidiopathic aplastic anaemia, idiopathic neutropenia,and chemotherapy-associated agranulocytosis.Antithyroid drug–induced agranulocytosis is diag-nosed at the QMH by paying careful attention to the drughistory of patients who present with fever. Not all pa-tients with agranulocytosis have fever or other symptomsof infection, however, and some patients can be totallyasymptomatic. Tajiri et al7 have suggested that continu-ing antithyroid drug treatment in patients with asymp-tomatic agranulocytosis might actually cause permanentdamage to the marrow. This suggestion raises the impor-tant issue of regularly monitoring the white blood cellcount in patients who are taking antithyroid drugs.7396      HKMJ Vol 5 No 4 December 1999Lee et alAsawa et al8 have recommended that the leukocytedifferential count be checked, as patients with a normalwhite blood cell count may have a low neutrophil count.8The practical difficulty, however, is that thyrotoxicosisis a very common disease and hence many patients takeantithyroid drugs. In addition, the white blood cell countcan be falsely reassuring if normal, or unnecessarilyworrisome if relatively low. It is therefore more practicaland more cost-effective for doctors to instruct patientswho are taking antithyroid drugs to have their whiteblood cell count checked if they have a fever or sorethroat, rather than to have routine regular monitoring.9Doctors should also have a high index of suspicion ofagranulocytosis when they encounter such patients.References1. Tavintharan S, Rajasoorya C, Chew LS. Carbimazole-inducedagranulocytosis—a report of 2 recent cases. SingaporeMed J 1997;38:386-7.2. Genet P, Pulik U, Lionnet F, Bremont C. Use of colony-stimulating factors for the treatment of carbimazole-inducedagranulocytosis [letter]. Am J Hematol 1994;47:334-5.3. Julia A, Olona M, Bueno J, et al. Drug-induced agranulo-cytosis: prognostic factors in a series of 168 episodes. Br JHaematol 1991;79:366-72.4. Sprikkelman A, de Wolf JT, Vellenga E. The applicationof hematopoietic growth factors in drug-induced agranulo-cytosis: a review of 70 Cases. Leukemia 1994;8:2031-6.5. Ng SC. Carbimazole-induced agranulocytosis treated withgranulocyte-macrophage colony stimulating factor—a casereport. Ann Acad Med Singapore 1995;24:465-6.6. Gerl A, Gerhartz H, Wilmanns W. GM-CSF for agranulo-cytosis [letter]. J Intern Med 1991;230:90-1.7. Tajiri J, Noguchi S, Okamura S, et al. Granulocyte colony-stimulating factor treatment of antithyroid drug–inducedgranulocytopenia. Arch Intern Med 1993;153:509-14.8. Asawa T, Arai M, Takeda T, Aizawa T, Yamada T, Onishi Y.Antithyroid drug-induced agranulocytosis: is routine whiteblood cell count effective for the detection [letter]? ArchIntern Med 1992:204-7.9. Sobel R, Glick S. Monitoring antithyroid therapy [letter].Arch Intern Med 1993;153:2797.

Antithyroid drug-induced agranulocytosis

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Antithyroid drug-induced agranulocytosis

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