Antithyroid Drug-Induced Agranulocytosis: State of the Art on Diagnosis and Management

Abstract

Agranulocytosis is a rare but serious complication of antithyroid drug therapy, and an up-to-date understanding of this topic is important. Both direct toxicity and immune-mediated responses have been described as possible mechanisms. Some major susceptibility loci have recently been identified, which may lead the diagnosis of agranulocytosis into a genomic era. Onset is acute and patients present with symptoms and signs of infection together with high fever. Clinical suspicion is pivotal and should prompt blood sampling. An absolute neutrophil count of <500/μl in the presence of antithyroid drugs establishes the diagnosis. The causative drug should immediately be stopped to prevent further damage. Treatment includes broad-spectrum antibiotics and granulocyte-colony stimulation factor in selected patients. Later, patients will need definitive treatment for hyperthyroidism, usually with radioactive iodine or surgery. The best way to avoid the mortality associated with antithyroid drug-induced agranulocytosis is patient education.

Fig. 1

Mechanisms behind the onset of antithyroid drug-induced agranulocytosis. a Direct toxicity: the oxidative process of the antithyroid drug is mediated by myeloperoxidase and cytochrome P450, generating reactive metabolites that will induce apoptosis either directly or via inflammasomes. b Immune-mediated toxicity: anti-neutrophil cytoplasmic antibodies may react against neutrophil antigens as proteinase 3, myeloperoxidase, and cathepsin G after neutrophils are primed and antigens migrate to the cell membrane. Anti-neutrophil cytoplasmic antibodies can also induce opsonization of neutrophils mediated by the complement system and react with myeloid precursors. ANCA anti-neutrophil cytoplasmic antibodies, CYP cytochrome P450, MPO myeloperoxidase

Fig. 2

Flowchart of the treatment of antithyroid drug-induced agranulocytosis. ATD antithyroid drug, iv intravenous, RAI radioactive iodine