Why test for chitotriosidase?
Chitotriosidase is primarily produced by activated macrophages and epithelial cells, and has a critical role in the context of infectious diseases.1,2 Disease activity in haematological and neurological disorders can be monitored based on chitotriosidase activity.3 In patients with Gaucher disease Type 1, chitotriosidase activity is markedly increased in the plasma.1 The total amount of stored glucocerebrosidase is associated with the concentration of chitotriosidase. Therefore, chitotriosidase activity reflects the degree of glucocerebrosidase overload in patients with Gaucher disease.1,4,5 A baseline evaluation of chitotriosidase activity is recommended in patients diagnosed with Gaucher disease.4-8
What is the chitotriosidase test?
Activity of chitotriosidase can be measured using EDTA plasma from patients with Gaucher disease.1 There is variability in chitotriosidase activity amongst patients with Gaucher disease, and mutations in the gene that encodes chitotriosidase (CHIT1) have been identified.9-13 Consequently, measurement of chitotriosidase activity may limit its use for between-patient comparisons, and it is recommended that chitotriosidase DNA mutational analysis is performed.7,8,11 Activity of chitotriosidase is >600-times higher in patients with Gaucher disease Type 1 (median [range], 12,824 [3122‒65,349] nmol/mL/h) compared with individuals without Gaucher disease (median [range], 20 [4‒76] nmol/mL/h). The main source of this enhanced chitotriosidase activity appears to be Gaucher cells.1
Chitotriosidase as a biomarker for paediatric Gaucher disease
A retrospective, cross-sectional study assessed the diagnostic test properties of chitotriosidase activity in 106 children aged ≤10 years who were referred to a single centre for lysosomal storage diseases. In this cohort, 30 patients were identified with Gaucher disease (median age, 4 years), of whom six were siblings from three families. The median (range) chitotriosidase activity of these patients was 12,655 (4693‒20,982) nmol/mL/h. Further analysis indicated that chitotriosidase activity >4000 nmol/mL/h was considered indicative of Gaucher disease compared with the other lysosomal storage diseases studied (sphingomyelinase deficiency [i.e. Niemann–Pick disease type A and B], Niemann–Pick disease type C, or miscellaneous). In terms of Gaucher disease type, patients with Gaucher disease Type 3 (n=9) had significantly higher chitotriosidase activity compared with patients with Gaucher disease Type 1 (n=19; p<0.0001). These data indicate that analysis of chitotriosidase activity may be useful in narrowing the differential diagnosis in comparable populations of children with a suspected lysosomal storage disease.14
Chitotriosidase as a biomarker for adult Gaucher disease Type 1
One study aimed to assess whether plasma chitotriosidase activity could act as a predictive biomarker of the clinical manifestations of Gaucher disease. In 80 adult patients with Gaucher disease Type 1 (51% male), who had not received enzyme replacement therapy, chitotriosidase activity was significantly correlated with haemoglobin levels (p=0.006), platelet count in those not splenectomised (p=0.001), liver volume (p<0.001), spleen volume (p<0.001) and bone marrow involvement (p<0.001). In 47 patients (n=13 splenectomised) treated with enzyme replacement therapy, a decline in chitotriosidase activity correlated with an increase in haemoglobin levels (p=0.007) and a reduction in liver (p<0.001) and spleen (p=0.01) volumes. However, no significant relationship between changes in chitotriosidase activity and platelet count (p=0.15) or bone marrow involvement (p=0.104) were observed in these patients.15
In 15 patients with long-term complications or associated conditions (bone complications, n=7; amyloidosis or multiple myeloma, n=4 [one patient also had bone complication]; hepatocellular carcinoma, n=4 [one patient also had bone complication]; and Parkinson’s disease, n=1), high levels of baseline plasma chitotriosidase activity were observed. Median values of chitotriosidase activity were 44,973 nmol/mL/h compared with 25,478 nmol/mL/h for 59 patients without long-term complications or conditions (p=0.002). Following approximately 2‒5 years of enzyme replacement therapy, chitotriosidase activity was shown to exponentially decline and stabilise, or reach a plateau. These findings indicate that plasma chitotriosidase activity is a valuable biomarker for the assessment and follow-up of patients with Gaucher disease Type 1.15
C-ANPROM/INT//7567; Date of preparation: September 2020
- Hollak CE, van Weely S, van Oers MH, et al. Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 1994; 93: 1288-1292.
- Kanneganti M, Kamba A, Mizoguchi E. Role of chitotriosidase (chitinase 1) under normal and disease conditions. J Epithel Biol Pharmacol 2012; 5: 1-9.
- Barone R, Sotgiu S, Musumeci S. Plasma chitotriosidase in health and pathology. Clin Lab 2007; 53: 321-333.
- German Society for Child and Youth Medicine Working Group on Pediatric Metabolic Disorders. Gaucher's disease guidelines. March 2006. Available at https://www.ggd-ev.de/wp-content/uploads/mgaucher-22-12-2007.pdf. Accessed September 2020.
- Haute Autorité de Santé. Gaucher disease: national diagnosis and treatment protocol. January 2007. Available at https://www.has-sante.fr/upload/docs/application/pdf/ven_gaucher_web.pdf. Accessed September 2020.
- The Belgian Working Group on Gaucher disease. Guidelines for diagnosis, treatment and monitoring of Gaucher's disease. May 2016. Available at https://cema.uza.be/static/documenten/informatie_metabole_ziekten/Belgian%20Expert%20Opinion%20for%20Diagnosis,%20Treatment%20an%20Monitoring%20of%20Gaucher.pdf. Accessed September 2020.
- Deegan P, Hughes D, Mehta A, et al. UK National Guideline for adult Gaucher disease. April 2005. Available at https://www.researchgate.net/publication/265282933_UK_National_Guideline_for_Adult_Gaucher_Disease_April_2005. Accessed September 2020.
- Fundaciόn Española para el Estudio y Tratamiento de la Enfermedad de Gaucher y otras Lisosomales. Medical care guide for patients with Type 1 Gaucher's disease. April 2011. Available at http://www.feeteg.org/docs/GC_Gaucher3.pdf. Accessed September 2020.
- Giraldo P, Cenarro A, Alfonso P, et al. Chitotriosidase genotype and plasma activity in patients type 1 Gaucher's disease and their relatives (carriers and non carriers). Haematologica 2001; 86: 977-984.
- Grace ME, Balwani M, Nazarenko I, et al. Type 1 Gaucher disease: null and hypomorphic novel chitotriosidase mutations-implications for diagnosis and therapeutic monitoring. Hum Mutat 2007; 28: 866-873.
- Bussink AP, Verhoek M, Vreede J, et al. Common G102S polymorphism in chitotriosidase differentially affects activity towards 4-methylumbelliferyl substrates. FEBS J 2009; 276: 5678-5688.
- Irun P, Alfonso P, Aznarez S, et al. Chitotriosidase variants in patients with Gaucher disease. Implications for diagnosis and therapeutic monitoring. Clin Biochem 2013; 46: 1804-1807.
- Sperb-Ludwig F, Heineck BL, Michelin-Tirelli K, et al. Chitotriosidase on treatment-naive patients with Gaucher disease: A genotype vs phenotype study. Clin Chim Acta 2019; 492: 1-6.
- Ries M, Schaefer E, Luhrs T, et al. Critical assessment of chitotriosidase analysis in the rational laboratory diagnosis of children with Gaucher disease and Niemann-Pick disease type A/B and C. J Inherit Metab Dis 2006; 29: 647-652.
- van Dussen L, Hendriks EJ, Groener JE, et al. Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy. J Inherit Metab Dis 2014; 37: 991-1001.