What is agranulocytosis and how does it present in patients with hyperthyroidism treated with methimazole (or propylthiouracil)?

What is Agranulocytosis in the Context of Antithyroid Drug Therapy?

Agranulocytosis is a life-threatening hematologic emergency defined as an absolute neutrophil count (ANC) below 500/mm³, occurring in approximately 0.2–0.5% of patients treated with methimazole or propylthiouracil, typically within the first 3 months of therapy. 1, 2

Definition and Laboratory Criteria

• Agranulocytosis is specifically defined as an ANC <500/mm³ in patients receiving antithyroid drugs 3
• The condition represents a severe form of neutropenia where the body's ability to fight infection is critically compromised 1, 2
• White blood cell counts at presentation typically range from 450 to 1,710/μL in documented cases 4

Clinical Presentation: Cardinal Warning Signs

Fever and sore throat are the hallmark early warning symptoms that demand immediate medical evaluation and complete blood count. 5, 1, 2

The characteristic symptom complex includes:

• Fever – present in 83% of cases, often the first manifestation 6
• Sore throat – occurs in 75% of cases as an early sign 5, 6
• Flu-like symptoms including generalized weakness, malaise, and chills 5
• Diarrhea may also occur in some patients 4

Timing and Risk Profile

• The median time from ATD initiation to agranulocytosis development is 30 days (range 20–40 days), with most cases occurring within the first 3 months 1, 2, 6
• Agranulocytosis can develop as late as 1,344 days after starting therapy, though this is uncommon 7
• Patients with amiodarone-induced thyrotoxicosis have a 5.70-fold higher risk of developing agranulocytosis when treated with ATDs compared to other causes of hyperthyroidism 8
• When ATD therapy is resumed after interruption, agranulocytosis can still develop, but typically not if the interruption was less than 5 months 9

Drug-Specific Characteristics

Methimazole tends to cause more severe agranulocytosis with lower nadir neutrophil counts (0.01 × 10⁹/L) compared to propylthiouracil (0.14 × 10⁹/L), though propylthiouracil carries additional risks of severe liver failure. 1, 2, 6

• Methimazole-induced agranulocytosis has a longer recovery time (9.32 ± 2.89 days) compared to propylthiouracil (5.60 ± 4.10 days) 6
• Cross-reactivity between methimazole and propylthiouracil can occur—agranulocytosis may persist despite switching from one drug to the other 4
• Both drugs carry FDA black box warnings for agranulocytosis 1, 2

Immediate Management Protocol

The moment agranulocytosis is confirmed, the antithyroid drug must be discontinued immediately, broad-spectrum intravenous antibiotics initiated, and granulocyte colony-stimulating factor (G-CSF) administered to accelerate neutrophil recovery. 3

Critical Action Steps:

• Stop the antithyroid drug immediately upon confirmation of ANC <500/mm³ 3, 1, 2
• Initiate broad-spectrum IV antibiotics empirically, even before culture results, due to high infection risk 3
• Administer G-CSF at 300 mcg/day intravenously to shorten recovery time 3
• Obtain daily complete blood counts with differential to monitor neutrophil recovery 3
• Institute infection surveillance protocols and consider hematology consultation 3

Recovery and Prognosis

• With prompt discontinuation of the offending drug and supportive care including G-CSF, recovery time ranges from 3 to 13 days 4
• Agranulocytosis is generally reversible when the antithyroid drug is stopped immediately 3, 1, 2
• All patients in reported case series recovered when appropriate management was instituted 4
• Hospital length of stay averages 12 days with costs approximating $2,810 6

Prevention Strategy: Patient Education Over Routine Monitoring

Patient education about fever and sore throat as warning symptoms is more effective and cost-efficient than routine complete blood count monitoring, because agranulocytosis onset is typically acute and symptomatic. 3

• Patients must be instructed to seek immediate medical attention if they develop fever, sore throat, or flu-like symptoms, especially within the first 3 months of treatment 3, 1, 2
• Routine CBC monitoring is not expected to prevent agranulocytosis due to its rapid and unpredictable onset 1
• However, obtaining a CBC when symptoms develop is essential for diagnosis 5, 4

Critical Pitfalls to Avoid

• Never delay discontinuation of the antithyroid drug while awaiting culture results or further testing—immediate cessation is mandatory 3, 1, 2
• Do not assume switching from methimazole to propylthiouracil (or vice versa) will be safe, as cross-reactivity can occur 4
• Avoid resuming the same antithyroid drug after an episode of agranulocytosis—definitive therapy with radioactive iodine or surgery should be pursued 3
• Do not rely on biochemical monitoring alone; patient-reported symptoms are the primary early warning system 1