Chitotriosidase Role in the Monitoring and Follow-up of Treatment in Gaucher Disease: A Review

Abstract

Gaucher disease (GD) is the most common lysosomal storage disorder, resulting from an inherited deficiency of the enzyme glucocerebrosidase with an accumulation of glucocerebroside within macrophages of the reticuloendothelial system. Since the introduction of enzyme replacement therapy (ERT), reproducible biomarkers have become essential for GD diagnosis and monitoring the treatment. For that, plasma chitotriosidase (ChT), an enzyme that secreted almost exclusively by activated macrophages, has emerged as the most powerful and most extensively validated. This review summarizes ChT biology, the pathophysiological basis of its elevation in GD, and the current evidence for its use in the diagnosis and, in particular, the monitoring and follow-up of enzyme replacement therapy in GD patients. Literatures demonstrated that ChT activity is elevated significantly in untreated GD patients relative to healthy individuals, which become declined sharply and progressively with ERT, most markedly during the first 6-12 months of treatment accompanying the reduction in visceral and hematological disease burden. Receiver Operating Characteristic (ROC) curve analyses across multiple cohorts, have shown that ChT achieves near-perfect sensitivity and specificity, both for distinguishing patients from controls and for differentiating successive stages of treatment, outperforming other candidate biomarkers such as tartrate-resistant acid phosphatase, angiotensin-converting enzyme, and ferritin. Important limitations remain, principally a common null polymorphism in the CHIT1 gene that abolishes enzymatic activity in a subset of the population, and substrate inhibition at high enzyme concentrations, both of which can complicate interpretation. Despite these caveats, ChT remains the single most useful biochemical parameter currently available for the routine monitoring and follow-up of enzyme replacement therapy in Gaucher disease and is recommended as a core component of the biomarker panel used in the long-term care of these patients.