4. II. 不良反應有關資料
11. 不良反應結果
A. 死亡，日期︰ 年 月 日，死亡原因︰
B. 危及生命 C. 導致病人住院
D. 造成永久性殘疾 E. 延長病人住院時間
F. 需作處置以防永久性傷害 G. 先天性畸形
H. 非嚴重不良反應（請敘述）
成大藥物不良反應通報表
4
1. 發生日期︰2013/04/17 2. 通報者獲知日期︰2013/04/21
4. 通報者資料
姓名︰陳秋縈
電話︰5693
屬性： 藥師
服務機構︰成大醫院
地址：台南市北區勝利路138號
職稱︰ 藥師
I. 病人基本資料
5.識別代號︰
（供通報者辨識用）
6. 性別︰ 男 女
7. 年齡︰22歲
8. 體重︰67.8 公斤
9. 身高︰175 公分
5. 其他相關資料
5
Present illness
• Graves’ disease with
thyrotoxic periodic paralysis
Medication
Methimazole 10 mg BID PO
Propranolol 10 mg BID PO
Loratadine 10 mg QD PO
Past History
• Allergic rhinitis
Drug Allergy Family History
• Bronchodilator: 心跳變快 • Not contribution
Social History
• Smoking (-)
• Betel nut (-)
• Drinking (-)
• Drug abuse (-)
6. ER
• Sudden onset limb & leg weakness
Muscle power: R’t>L’t, distal>proximal
• HR: 130 bpm, K: 2.0 mmol/L
Suspect thyrotoxic periodic paralysis
• KCl 20mEq IVD STAT
Propranolol 10mg PO STAT
• Slow K 8.06mEq 2 tab QID x 3 day
• Thyroid function test and OPD
follow up
NCKUH OPD
• Hyperthyroidism (lab data on 12/31)
TSH: <0.005 μIU/mL
TT3: 320.9 ng/dL, FT4: 5.10 ng/dL
Diagnosis: Thyrotoxic periodic paralysis
• Refillable prescription
Methimazole 10mg BID
Propranolol 10mg TID
• Slow K 8.06mEq BID x 7 days
CMUH-Taipei branch OPD
• Pruritus
• Shift Methimazole to
Propylthiouracil 10mg BID
NCKUH OPD
• (Lab data report on 02/14)
T3: 106.88 ng/dL, T4: 8.53 ug/dL
TSH: 0.07 uU/mL
Anti-TSH receptor antibody: 4.27 U/L
Graves’ disease
• Refillable prescription
Methimazole 10mg BID
Loratadine 10mg QD
Propranolol 10mg BID
通報事件之描述 (1)
102
2/21
2/06
1/03
12/30
6
7. NCKUH OPD
• Fever, sore throat since 04/17
• BT: 38.7℃
Injected tonsil with pus coating
Acute supportive tonsillitis
Suggested admission, patient refused
• Augmentin 875/125mg BID x 5 days
• Diclofenac 25mg QID x 5 days
ER
• Fever, sore throat
• Augmentin 875/125mg BID x 2 days
• Diclofenac 25mg QID x 2 days
• Oxethazaine/ Polymigel 5/244 mg
QID AC x 3 days
ER
• Fever, sore throat, chills
• BT: 39.5℃ , CRP: 348.8 mg/L
WBC: 1000/μL, ANC: 26/μL
Acute tonsillitis and agranulocytosis,
highly suspect methimazole induced
Admission
• Hold methimazole
• Throat swab and blood culture
• Cefepime 2000mg Q12H IVD
• Acetaminophen 500mg Q6H PRN
Lysine Acetylsalicylate 0.9g Q6H PRN
IVD
通報事件之描述 (2)
4/21
4/20
4/18
ANC= Absolute Neutrophil Count
Admission
7
8. • Intermittent chills with fever
• Rhinorrhea, cough with sputum
• WBC: 900/μL, ANC: 0/μL
• Vancomycin 1000 mg Q12H IVD
• G-CSF 300mcg QD SC
• Cough mixture 10 ml TID
• Throat swab culture report (4/21):
Klebsiella pneumonia
• No other infection focus
• Consult ENT
Chlorhexidine gargle for oral
hygiene
• WBC: 1000/μL, ANC: 380/μL
• Fever subside
• WBC: 10700/μL, ANC: 1564/μL
• Tonsil swelling and injective improving
• Stop G-CSF use
• Stable condition, No fever
Normal thyroid function
(Lab on 4/24) TSH 2.82 μIU/mL
TT3: 127.5 ng/dL, FT4: 0.908 ng/dL
Discharge medication
Cefuroxime 500mg Q12H PO
Acetaminophen 500mg Q6H PRN
通報事件之描述 (3)
4/26
4/25
4/24
4/28
4/29
4/30
4/21 Admission
8
GCSF= Granulocyte-colony Stimulating Factor
15. Which is causative Agents ?
15
4/171/03 2/06 2/21 21
Symptoms
fever
sore throat
Admission
Agranulocytosis
ANC: 26/μL
MMI PTU MMI
Propranolol
55 4
108
• PTU ?
Time to recovery after discontinuation: 1-2 weeks
• Propranolol vs MMI ?
MMI=Methimazole
PTU= Propylthiouracil
ANC= Absolute Neutrophil Count
1534
Relative risk (95% CI) Duration of drug use Our patient
Methimazole 230.9 (120.4–453.5) Usually within the first 3 months use 55 days
Propranolol 2.5 (1.1–6.1) Association for short-term use
( < 28 days)
use 108 days
Clin Pharmacol Ther. 1991 Mar;49(3):330-41.
JAMA. 1973 Mar 19;223(12):1376-7. Ann Intern Med. 2007;146:657-665
18. Antithyroid drugs
N Engl J Med. 2005;352:905-917. 18
Thionamide
Methimazole (MMI), carbimazole, and propylthiouracil (PTU)
Mechanism of action
Inhibits thyroid hormone synthesis by interfering with iodine
incorporation
Inhibit peripheral deiodination of T4 to T3 (only PTU)
Adverse reactions
Minor Major
Skin reactions 4–6% Polyarthritis 1–2%
Arthralgias 1–5% ANCA-positive vasculitis Rare
Gastrointestinal effects 1–5% Agranulocytosis 0.1–0.5%
Abnormal sense of taste or smell Rare Immunoallergic hepatitis 0.1–1%
Sialadenitis Very rare Cholestasis, hypoglycemia,
pancreatitis, hypoprothrombinemia,
thrombocytopenia, aplastic anemia
Rare
ANCA= Antineutrophil Cytoplasmic Antibody
19. Skin reactions of antithyroid drugs
N Engl J Med. 2005;352:905-917.
Thyroid. 2011;21(6):593. 19
Incidence
Equal frequency for MMI and PTU, approximately 5%
Cross-reactivity between PTU and MMI are up to 50%
Associated symptoms
Pruritus, rash, urticarial
Management
Mild skin reactions can be treated with antihistamine therapy without
stopping MMI or PTU
For serious allergic reactions, therapy should be discontinued and prescribing
another thionamide is not recommended
20. Choice of drug in long-term therapy
Thyroid. 2009 Jul;19(7):673-4
J Clin Endocrinol Metab. 1987;65(4):719.
Thyroid. 2004;14(7):525
Clin Endocrinol (Oxf). 2004;60(6):671.
J Clin Endocrinol Metab. 2009;94(6):1881.
ANCA= Antineutrophil Cytoplasmic Antibody
ATA= American Thyroid Association
FDA= Food and Drug Administration 20
ATA and FDA recommended MMI as a first-line drug
More quickly reverse hyperthyroidism
• Time to achieve euthyroidism
MMI 10 mg TID: average 5.8 weeks, PTU 100 mg TID: average 16.8 weeks
Once-daily dosing and better compliance
• Half-life
MMI 4-6 hrs, PTU 75 mins
Less likely to be associated with failure of radioiodine therapy
• Cured by a 10 mCi dose of subsequent radioiodine therapy
pretreated with MMI: 78% of patients, pretreated with PTU: 32% of patients
Less toxicity
• ANCA-positive vasculitis and severe hepatotoxicity were more strongly associated with
PTU than MMI
21. Antithyroid drug-induced agranulocytosis
Thyroid 2004;14:459-62.
N Engl J Med. 2005;352:905-917.
Clin Endocrinol (Oxf). 2004 Nov;61(5):589-94.
ANC= absolute neutrophil count
MMI=Methimazole
PTU= Propylthiouracil 21
Definition
Severe reduction of granulocytes in the peripheral blood with ANC < 500/μL
Incidence
MMI: 0.35 %, PTU: 0.37 %
May occur in any age group, without gender difference
Outcome
Severe (mortality rate of untreated patients: 6% )
Associated symptoms
Most common: sudden onset of fever and sore throat
Others: chills, cough, rhinorrhea, malaise, gingivitis, oral ulcer, pharyngitis or
tonsillitis, dysphagia
Our patient
ANC: 26/μL
Our patient
Fever, sore throat,
chills, tonsillitis
22. Onset of agranulocytosis
Am J Med 1954;17:36-40.
Thyroid 2004;14:459-62.
N Engl J Med. 2005;352:905-917.
Clin Endocrinol (Oxf). 2004 Nov;61(5):589-94.
J Clin Endocrinol Metab. 2012 Jan;97(1):E49-53.
Endocr Pract. 2012;18:e69-e72 22
Rarely appeared before the 10th day of
treatment
Due to slow accumulation of enough drug
to induce a reaction in bone marrow tissue
Usually occurs within the first 3 months
after initiation
Can also be delayed onset
eg. 6 years of MMI
May also occur after renewed exposure
following previous course of treatment
The cumulative incidence of agranulocytosis
Average time to onset:
69 days (range 11-233 days)
Our patient: second exposure of MMI 55 days
23. Possible mechanism
Expert Opin. Drug Saf. (2007) 6(3):323-335N
Engl J Med 2005;352: 905-17.
J Clin Endocrinol Metab 1984;58:868-72.
23
Immunological reaction
Appearance of antineutrophil antibodies in the serum of affected patients
Leading to rapid destruction of mature neutrophil granulocytes and their
bone marrow precursors
Direct cytotoxic effect
Major mechanism
24. Possible risk factors (1)
24
Dose Ref.
• Incidence with initial MMI dose of 30 mg (4.11%) significantly higher than 15 mg
(0.36%)
1
• A retrospective review of 21,800 patients receiving antithyroid drugs
(duration, 15.7 ± 8.4 months)
0 patient developed agranulocytosis with MMI dose < 20 mg/day (n=15,412)
5 patients developed agranulocytosis with MMI dose ≥ 20mg/day (n=5,428)
2
• MMI dose ≥ 40 mg/day were associated with 8.6-fold increased risk of agranulocytosis
than dose < 40 mg/day (p <0.001)
• The prevalence with PTU was dose-independent
3
1. Endocr J. 2007;54:39-43.
2. Int J Endocrinol Metab. 2006;4:210-215.
3. Ann Intern Med. 1983;98(1):26.
4. Chang Gung Med J 2007;30:242-8
MMI=Methimazole
PTU= Propylthiouracil
• A case series in Taiwan
in 9 patients developed agranulcytosis
MMI or carbimazole dose 15-30 mg/day
(mean±SD: 22.78±7.12 mg/day)
4
Lower dose reported
Our patient
MMI 10 mg BID
25. Possible risk factors (2)
25
Age Ref.
• The relative risk of developing agranulocytosis in patients over age 40 was
6.4 times that among younger patients (p <0.001)
1
Genetic factor Ref.
• A case-control study in Japanese people
the HLA DRB1*08032 allele appears to be strongly associated with
susceptibility to methimazole-induced agranulocytosis
2
• Case report
Methimazole-induced agranulocytosis in a mother and her young daughter
3
1. Ann Intern Med. 1983;98(1):26.
2. Ann Intern Med. 1996;124(5):490.
3. Int J Endocrinol Metab 2006; 4: 113-116.
26. Prognostic factors
Ann Intern Med. 2007;146:657-665.
Expert Opin Drug Saf. 2007;6(3):323–335.
QJM 2001;94:423-8.
26
Poor prognostic criterion
Age > 65 years
Neutrophil count < 100 cells /mm3
Higher rate of localized infections (59 vs 39%, p < 0.001),
sepsis (20 vs 6%, p < 0.001) and fatal complications (10 vs 3%, p < 0.001)
Severe clinical infection, such as sepsis or shock
Severe underlying disease or comorbidity
Bone marrow morphology
The speed of neutrophil recovery depends on the number of myeloid
precursor cells that are present in the bone marrow
Severe depression of myeloid precursors suggests a prolonged recovery time
and a failure to respond to G-CSF
GCSF= Granulocyte-colony Stimulating Factor
Our patient
• 22 year-old
• ANC: 26/μL
• Acute supportive
tonsillitis
27. Management
J Endocrinol Invest. 1994;17(1):29.
Am J Hematol. 2009 Jul;84(7):428-34.
Br J Haematol. 2010;150(1):3.
27
Withdrawal of the offending drug
Regardless of whether the patient is symptomatic
Recovery occurred within 1 to 2 weeks (ranges 7-56 days) without
treatment
Antimicrobial therapy
Empirical broad-spectrum antibiotic in patients with fever or infection sign
Granulocyte colony-stimulating factor
Efficacy is not conclusively proven in non oncology setting
Shorten recovery times, length of hospitalization, and less antibiotic use in
non-randomized studies
Recommend to administer in poor prognosis patient
Usual dose: 5 mcg/kg/day
31. 藥物不良反應相關性評估
Naranjo Score
Clin. Pharmacol. Ther. 1981;30 (2): 239–45. 31
Yes No
Do not
know
1. Are there previous conclusive reports on this reaction?
此不良反應是否有確定的研究報告？
+1 0 0
2. Did the adverse events appear after the suspected drug was given?
此不良反應是否發生於服藥之後？
Symptoms onset: 55 days, agranulocytosis detected: 59 days
+2 -1 0
3. Did the adverse reaction improve when the drug was discontinued or a
specific antagonist was given?
當停藥或使用此藥之解藥，不良反應是否減輕？
Recovery time: 9 days after stop MMI and G-CSF use for 5 days
+1 0 0
4. Did the adverse reaction appear when the drug was readministered?
再次服用此藥，同樣的不良反應是否再度發生?
+2 -1 0
5. Are there alternative causes that could have caused the reaction?
有沒有其他原因(此藥以外)可以引起同樣之不良反應？
Propranolol: lower risk than MMI, and usually occurred soon after
initiation
-1 +2 0
32. 藥物不良反應相關性評估
Naranjo Score
Clin. Pharmacol. Ther. 1981;30 (2): 239–45. 32
Yes No
Do not
know
6. Did the reaction reappear when a placebo was given?
當給予安慰劑時，此項不良反應是否也會再度發生?
-1 +1 0
7. Was the drug detected in any body fluid in toxic concentrations?
此藥物的血中濃度是否達到中毒劑量？
+1 0 0
8. Was the reaction more severe when the dose was increased, or less
severe when the dose was decreased?
對此病人而言，藥物劑量與不良反應的程度是否成正向關係？
+1 0 0
9. Did the patient have a similar reaction to the same or similar drugs in
any previous exposure?
病人過去對同樣或類似藥物是否也產生同樣的不良反應？
MMI for 34 days, PTU for 15 days
+1 0 0
10.Was the adverse event confirmed by any objective evidence?
此不良反應是否有任何客觀證據可證實?
+1 0 0
總分 4 ；判斷屬於下列何者：
□ 9分,確定; □ 5-8分,極可能; ■ 1-4分,可能; □ 0分,存疑
33. 成大醫院藥物不良反應評估表(2)
33
可能性評估: □確定 ( 9分) □極可能(5-8分) ■可能(1-4分) □存疑(0分)
嚴重程度： □死亡
□危及生命 □永久性殘疾 □先天性畸形
■需做處置以防永久性傷害
□導致住院 □增加住院日 □需額外的醫療處置 □自行緩解
藥物不良反應型態：□ Type A (Pharmacological) ■ Type B (Idiosyncratic)
報告來源： □ 經由藥師訪視、住院藥品調配單或病歷記錄
□ 經由其他的預警因素如：緊急處方、實驗數值、報表或電腦
查詢等
□ 其他醫事人員通告如：護士、醫師等
■ 經由其他醫事人員填寫之藥物不良反應報告表
34. Preventable ADR ?
J. Clin. Gastroenterol. (1997) 24:180-183.
N Engl J Med. 2005;352:905-917.
thyroid. 2011;21(6):593.
Routine monitoring is controversial and not recommended by
some authorities
Low incidence of agranulocytosis
Agranulocytosis can occur suddenly (within 1-2 day)
Transient, reversable mild granulocytopenia
(granulocyte count < 1500/mm3)
- Occasionally occurs as a manifestation thyrotoxicosis itself, and
occasionally in patients treated with antithyroid drugs
- Does not usually increase the risk of infection and herald the onset of
agranulocytosis
ATA guidelines do not recommend routine monitoring
34
35. Prevention and screening
Thyroid. 2011;21(6):593.
35
Recommendation
A baseline differential WBC count should be obtained before initiation
of therapy
White cell count with differential should be obtained immediately and
the drug discontinued at the earliest sign of a sore throat or other
infection
Patient education the most cost-effective method
All patients should be educated to discontinue the antithyroid drug
and contact a physician immediately if fever or sore throat develops,
especially within the first 3 months of medication
36. Alternative treatment options
Thyroid. 2011;21(6):593.
N Engl J Med. 2005;352:905-917.
36
Substitution with another thionamide is contraindicated
Carbimazole is identical to methimazole is rapidly metabolized to
methimazole in the liver after absorption
50% chance of cross-sensitivity between propylthiouracil and
methimazole
Agranulocytosis is a severe and possible fatal ADR
Radioiodine therapy or surgery may be better choices than the
use of another type of antithyroid drug
37. 紀錄者意見
37
There is a reasonable time relationship between drug intake
and agranulocytosis developed
Propranolol can also cause agranulocytosis, but MMI has a
higher risk and clinical features consistent with our patient
This is a severe and possible fatal ADR with significant cross
sensitivity between MMI and PTU, so this patient should not
rechallenge these drugs in future
Radioiodine therapy may be an alternative treatment option
38. Take home message
38
Incidence Management
• MMI: 0.35%, PTU: 0.37% • G-CSF therapy to patients results in a
good prognosis
• Recommend to administer in poor
prognosis patient
Onset
• Most frequently in the first 3 months
• But can be delayed onset
Presentation Prevention and screening
• Fever and sore throat are most
common • Early detection is the key factor
Educating patients about the common
symptoms of agranulocytosis may
contribute to an early diagnosis
The most cost-effective method
Possible Risk factors
• Higher dose
• Age > 40 y/o
• Genetic factor
39. Thanks for your attention!!!
Any questions and comments are welcome!
39
40. Thyrotoxic periodic paralysis
40
Thyrotoxic periodic paralysis
Diagnosis and
associated features
Paralytic attack that is associated with hypokalemia and hyperthyroidism (low TSH
with high T4 or high T3)
Mechanism Thyroid hormone increases tissue responsiveness to beta-adrenergic stimulation
Increases Na-K ATPase activity on the skeletal muscle membrane
Drive potassium into cells
Hyperpolarization of the muscle membrane Paralyses
Etiology Thyrotoxicosis
Possible inherited predisposition
Age at onset >20 years
Attack duration Hours to days
Epidemiology Highest incidence in Asians, men > women
Precipitants Rest after strenuous exercise
High-carbohydrate load
Stress
Preventive treatment Euthyroid state
Propranolol
41. 41
Hypokalemic Periodic
Paralysis
Thyrotoxic Periodic
Paralysis
Hyperkalemic Periodic
Paralysis
Andersen Syndr
Age at onset First or second decade >20 years First decade First or second dec
Attack frequency Infrequent (a few times a
year)
Infrequent Frequent (up to several a
day)
Monthly
Attack duration Hours to days Hours to days Minutes to hours Days
Precipitants Exercise
Carbohydrate load
Stress
Exercise
Carbohydrate load
Stress
Exercise
Fasting
Stress
K-rich food
Rest after exercise
Potassium level during
attack
Low Low Normal or elevated Low, normal, or ele
Associated features Later onset myopathy Symptoms of
thyrotoxicosis
Low TSH with high T4 or
high T3
Myotonia on
examination and/or EMG
Later onset myopathy
Dysmorphic featur
Ventricular arrhyth
Long QT interval
Etiology Autosomal dominant
inherited defect in calcium
or sodium ion channel on
muscle membrane
Thyrotoxicosis
Possible inherited
predisposition
Autosomal dominant
inherited defect of
sodium ion channel on
muscle membrane
Autosomal domina
inherited defect of
inward rectifying
potassium channel
Penetrance Nonpenetrance common,
especially in women
High Nonpenetrance an
incomplete penetr
common
Epidemiology Clinical expression in men
more frequent than women
Highest incidence in
Asians and in men more
than women
Sexes equally affected Marked intrafamili
phenotypic variatio
Preventive treatment Carbonic anhydrase
inhibitors
Potassium-sparing diuretics
Euthyroid state
Propranolol
Carbonic anhydrase
inhibitors
Thiazide diuretics
Inhaled beta-agonists as
Carbonic anhydras
inhibitors
44. G-CSF
44
Mechanism of Action
Stimulates the production, maturation, and activation of neutrophils;
filgrastim activates neutrophils to increase both their migration and
cytotoxicity.
Pharmacodynamics/Kinetics
Onset of action: ~24 hours; plateaus in 3-5 days
Duration: Neutrophil counts generally return to baseline within 4 days
Absorption: SubQ: 100%
Distribution: Vd: 150 mL/kg; no evidence of drug accumulation over a
11- to 20-day period
Metabolism: Systemically degraded
Half-life elimination: 1.8-3.5 hours
Time to peak, serum: SubQ: 2-8 hours
45. A case of delayed onset of agranulocytosis
Endocr Pract. 2012;18:e69-e72
A 53-year-old woman had been treated continuously with antithyroid drugs
for 11 years– PTU for 5 years and MMI for 6 years—before the onset of
agranulocytosis
Case report
Drug-induced agranulocytosis can occur after a very prolonged period of
low-dose treatment with antithyroid medications
1998/02
PTU 100-150 mg/day
2003/07 2009/03
AgranulocytosisMMI 20-30 mg
2004/02
MMI 5-15 mg
46. Risk factors- initial dose
Endocr J. 2007;54:39-43.
Results
514 patients with Graves’ disease in Japan
9 patients (1.75%) developed agranulocytosis due to MMI treatment
Statistically significant difference in
agranulocytosis incidence between
patients receiving 30 mg MMI and those
receiving 15 mg MMI
47. Risk factors- dose
Int J Endocrinol Metab. 2006;4:210-215.
21800 received
antithyroid drugs
MMI
20840
Low doses
(<20mg/day)
15412
Agranulocytosis
0
High doses
(≥20mg/day)
5428
Agranulocytosis
5
PTU
960
Agranulocytosis
2
No patients receiving a methimazole dose < 20 mg daily developed agranulocytosis
• A retrospective review of 21,800 patients receiving ATDs (duration, 15.7 ± 8.4
months)
48. Risk factors- dose
Int J Endocrinol Metab. 2006;4:210-215.
The majority of agranulocytosis occurred within the first few weeks of ATD therapy
49. Risk factors- Age and Drug Dose
Ann Intern Med. 1983;98(1):26.
Objective
Investigated the role of patient age, dosage and type of thionamide used, on
development of agranulocytosis
Results
Higher doses of MMI (> 40 mg/day) were associated with 8.6-fold increased
risk of agranulocytosis (p <0.001)
Age over 40 years caused higher risk of development of agranulocytosis
The prevalence with PTU was dose-independent
Agranulocytosis Associated with Antithyroid Drugs:
Effects of Patient Age and Drug Dose
DAVID S. COOPER, M.D.; DAVID GOLDMINZ, B.S.; ANN A. LEVIN, M.S.; PAUL W. LADENSON, M.D.;
GILBERT H. DANIELS, M.D.; MARK E. MOLITCH, M.D.; and E. CHESTER RIDGWAY, M.D.
50. Risk factors- genetics
Ann Intern Med. 1996;124(5):490.
A case-control study in japanese people
Objective
To determine the possible role of genetic factors in the development of
methimazole-associated agranulocytosis in patients with graves disease
Results
Among japanese patients with graves' disease, the HLA DRB1*08032 allele
appears to be strongly associated with susceptibility to methimazole-induced
agranulocytosis
Association between the DRB1*08032 Histocompatibility Antigen
and Methimazole-Induced Agranulocytosis in Japanese Patients
with Graves Disease
Hajime Tamai, MD; Tohru Sudo, MD; Akinori Kimura, MD; Toshio Mukuta, MD; Sunao Matsubayashi,
MD; Kanji Kuma, MD; Shigenobu Nagataki, MD; and Takehiko Sasazuki, MD
51. Risk factors- genetics
Ann Intern Med. 1996;124(5):490.
A case-control study in japanese people
Objective
To determine the possible role of genetic factors in the development of
methimazole-associated agranulocytosis in patients with graves disease
Results
Among japanese patients with graves' disease, the HLA DRB1*08032 allele
appears to be strongly associated with susceptibility to methimazole-induced
agranulocytosis
Association between the DRB1*08032 Histocompatibility Antigen
and Methimazole-Induced Agranulocytosis in Japanese Patients
with Graves Disease
Hajime Tamai, MD; Tohru Sudo, MD; Akinori Kimura, MD; Toshio Mukuta, MD; Sunao Matsubayashi,
MD; Kanji Kuma, MD; Shigenobu Nagataki, MD; and Takehiko Sasazuki, MD
Limitation of clinical utility
• HLA typing is impractical-time and cost
• Result indicates susceptibility only in japanese people
• Positive result for a specific allele does not imply that methimazole should be
withheld in patients with Graves hyperthyroidism, because of sufficiently low
frequency of agranulocytosis in patients with these alleles
52. Risk factors- genetics
Int J Endocrinol Metab 2006; 4: 113-116
It seems reasonable to avoid the use of thionamide derivates in
hyperthyroid relatives of patients who have had thionamide-
induced agranulocytosis
53. Suggest PTU instead of MMI
53
In pregnant women during their first trimester
In patients with life-threatening thyrotoxicosis or thyroid storm
Because of PTU’s ability to inhibit peripheral conversion of T4 to T3
In patients with adverse reactions to MMI who are not
candidates for radioiodine or surgery
Other than agranulocytosis
54. Rate of prolonged remission
54
20-30 % of patients treated with a thionamide for one to two
years
Increased likelihood of remission
Initially TSH-receptor antibody-negative (77% vs 36%)
Disappearance of tsh-receptor antibodies during thionamide therapy
Age > 40 y/o (48% vs 33%, p= 0.01)
Female sex (40% vs 20 %, p< 0.01)
55. Which is causative Agents
55
MMI 10mg BID PTU 10mg TID MMI 10mg BID
Propranolol 10mg TID BID
4/171/03 2/06 2/21 21
Fever, sore throat Admission
Agranulocytosis
ANC: 26/μL
MMI=Methimazole PTU= Propylthiouracil ANC= absolute neutrophil count
-4 day-59 day day 1
56. Propranolol vs MMI ?
Arch Intern Med. 1999;159:369-74.
Clin Pharmacol Ther. 1991;49:330-41.
JAMA. 1973 Mar 19;223(12):1376-7
56
Relative risk (95% CI) Duration of drug use Our patient
Methimazole 230.9 (120.4–453.5) Usually within the first 3 months use 55 days
Propranolol 2.5 (1.1–6.1) Risks appeared to be highest
shortly after initiation
10 mg tid/bid
for 108 days
A case report
A 64 year-old man with arrhythmia developed
agranulocytosis after 6 days of propranolol 40
mg Q4H use
A population-based case-control study in Europe
Duration (days) Exoposed c
(n=22)
< 28 7 (32%)
28-89 6 (27%)
≥ 90 9 (41%)
nolol, among a total of 22 exposed cases, 7 (32%)
been exposed for less than 28 days, whereas the
esponding data for the exposed control subjects
e 1 of 26 (4%). Th
57. Cases comparison
1. Q J Med 1999; 92:455-461
2. J Chin Med Assoc 2009; 72: 395-401.
3. Chang Gung Med J 1991;14:168-73
57
Taiwan1 Taiwan2 Taiwan3 Our Case
Age/sex 27/M 53/F 50/F 22/M
Disease Graves’ disease Graves’ disease Graves’ disease Grave’s disease
MMI dose 30 mg/day 30 mg/day 30 mg/day 20 mg/day
Treatment
duration
61 days 46 days
Second exposure
23 days
Second exposure
59 days
Symptoms
Fever, sore throat,
chills
Fever, sore throat,
diarrhea
NM
Fever, sore throat,
chills
Clinical
diagnosis
Acute tonsillitis NM NM Acute tonsillitis
Initial
WBC/ANC (/μL)
850/0 450/0 1700/34 1000/26
G-CSF use + + - +
Recovery 9 days 7 days 12 days 10 days
NM= Not mentioned
