Plasma chitotriosidase in male Fabry patients: a marker for monitoring lipid-laden macrophages and their correction by enzyme replacement therapy.

Increased plasma chitotriosidase is a well established surrogate marker for the occurrence of lipid-laden macrophages in the glycosphingolipidosis Gaucher disease. The complete lack of surrogate markers for Fabry disease, X-linked globotriaosylceramidosis stemming from deficiency in the lysosomal alpha-galactosidase A (AGA), prompted us to study chitotriosidase in this disorder. In male Fabry patients plasma chitotriosidase is significantly elevated, consistent with the presence of lipid-laden macrophages in several tissues. Increased levels are detectable at very young age and precede clinical manifestations. No strict correlation exists with severity of disease manifestations. Upon therapy with either of the two available recombinant AGA preparations, plasma chitotriosidase levels are nicely normalized in male Fabry patients. However, in patients developing neutralizing antibodies towards AGA, reduction in plasma chitotriosidase is hampered. In sharp contrast to the situation in male patients, females heterozygous for AGA deficiency show no significantly elevated plasma chitotriosidase. This suggests that circulating endogenous AGA in heterozygotes is sufficient to supplement enzyme-deficient macrophages. In conclusion, for the first time a biological marker for lipid-laden cells in Fabry patients is demonstrated; elevated plasma chitotriosidase levels reflecting lipid-laden macrophages. Corrections in this marker illustrate the efficacy of enzyme replacement therapy in clearing the lipid accumulation in this particular cell type.