agrannulocytosis is rare condition that can happen due to these drugs.it very important to have index of suspicion to pick this problem.surgery is always the solution where there is no Radio iodine treatment.

1. Antithyroid drug-induced
agranulocytosis
Prepared by: Endale(GSR IV)
Moderated by: Dr.Endale(General &Endocrine
surgeon)

2. ……….
Thionamide
Methimazole (MMI), carbimazole, and
propylthiouracil (PTU)
Mechanism of action
Inhibits thyroid hormone synthesis by inhibit
peripheral de iodination of T4 to T3 (only PTU)
interfering with iodine

3. 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 senseof taste or smell Rare lmmunoallergic hepatitis 0.1-1%
Sialadenitis Very rare Cholestasis, hypoglycemia, Rare
pancreatitis, hypoprothrombinemia,
thrombocytopenia, aplastic anemia

4. ………
Incidence
• Equal frequency for MMI and PTU, approximately 5% Cross-reactivity between PTU and MMI
are up to 50%
Associated symptoms
Pruritus, rash, urticaria!
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

5. ATA and FDA recommended MM/ as
a first-line drug
More quickly reverse hyperthyroidism
 Time to achieve euthyroidism
MMI 10 mg TIO: average 5.8 weeks, PTU 100 mg TIO: 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

6. Antithyroid drug-induced
agranulocytosis
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

7. Definition

8. …………
 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

9. ………
Average time to onset:
69 days (range 11-233 days)
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

10. ……….
Can also be delayed onset
E.g. 6 years of MMI
May also occur after renewed exposure
following previous course of treatment

11. Pathophysiology
A. Immunological reaction Major mechanism
Appearance of antineutrophil antibodies in
the serum of affected patients
 Leading to rapid destruction of mature
neutrophil granulocytes and their bone
marrow precursors
A. Hapten mechanism
Immune-complex mechanism
Autoimmune mechanism
B. Direct cytotoxicity mechanism

12. Risk factors
1.Dose
Incidence with initial MMI dose of 30 mg
(4.11%) significantly higher than 15 mg
(0.36%)
 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

13. Cont.…
2.Age
The relative risk of developing agranulocytosis
in patients over age 40 was
6.4 times that among younger patients (p <0.001)
3.Genetic factor
A case-control study in Japanese people:
the HLA DRBl *08032 allele appears to be strongly
associated with susceptibility to methimazole-
induced agranulocytosis

14. Prognostic factors
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

15. Management
A. Withdrawal of the offending drug
Regardless of whether the patient is symptomatic
Recovery occurred within 1to2 weeks (ranges 7-56 days) without treatment
B• Antimicrobial therapy
Empirical broad-spectrum antibiotic in patients with fever or infection sign
C• 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 prognostic patients
Usualdose:5mcg/kg/day

16. Monitoring & f/up
• Routine monitoring is controversial and not recommended by ATA &
some authorities.B/c
 Low incidence of agranulocytosis
 Agranulocytosis can occur suddenly (within 1-2 day) Transient, reversible
mild granulocytopenia
 (granulocyte count< 1500/mm3)
1. Occasionally occurs as a manifestation thyrotoxicosis itself, and
occasionally in patients treated with Antithyroid drugs
2. Does not usually increase the risk of infection and herald the onset of
agranulocytosis

17. Recommendations
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.

18. References
• Vicente, N., Cardoso, L., Barros, L., & Carrilho, F.
(2017). Antithyroid Drug-Induced
Agranulocytosis: State of the Art on Diagnosis and
Management. Drugs in R&D, 17(1), 91–96.
• Nakamura, H., Ide, A., Kudo, T., Nishihara, E., Ito,
M., & Miyauchi, A. (2016). Periodic Granulocyte
Count Measuring Is Useful for Detecting
Asymptomatic Agranulocytosis in Antithyroid
Drug-Treated Patients with Graves’ Disease.
European Thyroid Journal, 5(4), 253–260.