Metamizole is a widely prescribed
NSAID with excellent
analgesic and
antipyretic properties. Although very effective, it is banned in some countries because of the risk for severe
agranulocytosis. We here describe three patients with
metamizole-associated
agranulocytosis. Patient #1 suffered from
agranulocytosis and
tonsillitis followed by
severe sepsis by Streptococcus pneumoniae and Epstein-Barr virus reactivation. Her dizygotic twin sister (patient #2) also suffered from
agranulocytosis after a surgical intervention. Patient #3 initially had a
tonsillitis and also developed
neutropenia after
metamizole intake. For all patients, pharmacogenetic diagnostic for the genes
CYP2C9,
CYP2C19 and NAT2, which are involved in
metamizole metabolism and degradation of toxic metabolites, was initiated. Pharmacogenetic analysis revealed NAT2 slow acetylator phenotype in all three patients. Additionally, patient #2 is an intermediate metabolizer for
CYP2C19 and patient #3 is a poor metabolizer for
CYP2C9. Impairment of these
enzymes causes a reduced degradation of toxic metabolites, for example, 4-methylaminoantipyrine (4-MAA) or
4-aminoantipyrine. The metabolite 4-MAA can complex with
hemin, which is an early breakdown product during
hemolysis.
Hemolysis is often observed during invasive
infections or after
surgical procedures. It is known that the 4-MAA/
hemin complex can induce cytotoxicity in the bone marrow and interrupt granulocyte maturation. In conclusion,
metamizole-induced
agranulocytosis most likely was a consequence of the underlying genetical predisposition, that is, polymorphisms in the genes NAT2,
CYP2C9 and
CYP2C19.
Hemolysis may have increased the toxicity of
metamizole metabolites.