Journal of Inherited Metabolic Disease

, Volume 37, Issue 6, pp 991–1001 | Cite as

Value of plasma chitotriosidase to assess non-neuronopathic Gaucher disease severity and progression in the era of enzyme replacement therapy

  • L. van Dussen
  • E. J. Hendriks
  • J. E. M. Groener
  • R. G. Boot
  • C. E. M. Hollak
  • J. M. F. G. Aerts
Original Article


Gaucher disease (GD) is caused by deficiency of the enzyme glucocerebrosidase catalysing the regular lysosomal degradation of glucosylceramide. In the common non-neuropathic variant of GD, glucosylceramide-laden macrophages (Gaucher cells) accumulate in various tissues. Gaucher cells secrete chitotriosidase, an active chitinase, resulting in increased plasma chitotriosidase levels, which can be sensitively monitored by an enzyme activity assay. Plasma chitotriosidase is a rough estimate of body burden of Gaucher cells. Non-neuronopathic GD is presently treated by enzyme replacement therapy (ERT) and substrate reduction therapy (SRT). We addressed the question whether plasma chitotriosidase acts as (predictive) marker of clinical manifestations in non-neuronopathic GD patients receiving treatment. Reductions in plasma chitotriosidase during therapy correlated with corrections in liver and spleen volumes and showed positive trends with improvements in haemoglobin and platelet count and bone marrow composition. The occurrence of long-term complications and associated conditions such as multiple myeloma, bone complications, Parkinson’s disease, hepatocellular carcinoma and pulmonary hypertension positively correlated with the plasma chitotriosidase level pre-therapy, the average plasma chitotriosidase during 3 years of ERT and the residual plasma chitotriosidase after 2 years of ERT. In summary, plasma chitotriosidase is a valuable marker in the assessment and follow-up of GD patients.

Supplementary material

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  1. Aerts JM, Hollak CE (1997) Plasma and metabolic abnormalities in Gaucher’s disease. Baillieres Clin Haematol 10(4):691–709PubMedCrossRefGoogle Scholar
  2. Aerts JM, Hollak CE, van Breemen M, Maas M, Groener JE, Boot RG (2005) Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases. Acta Paediatr Suppl 94(447):43–46PubMedCrossRefGoogle Scholar
  3. Aerts JM, Kallemeijn WW, Wegdam W et al (2011) Biomarkers in the diagnosis of lysosomal storage disorders: proteins, lipids, and inhibodies. J Inherit Metab Dis 34(3):605–619PubMedCrossRefPubMedCentralGoogle Scholar
  4. Aguilera B, Ghauharali-van der Vlugt K, Helmond MT et al (2003) Transglycosidase activity of chitotriosidase: improved enzymatic assay for the human macrophage chitinase. J Biol Chem 278(42):40911–40916PubMedCrossRefGoogle Scholar
  5. Barton NW, Furbish FS, Murray GJ, Garfield M, Brady RO (1990) Therapeutic response to intravenous infusions of glucocerebrosidase in a patient with Gaucher disease. Proc Natl Acad Sci U S A 87(5):1913–1916PubMedCrossRefPubMedCentralGoogle Scholar
  6. Barton NW, Brady RO, Dambrosia JM et al (1991) Replacement therapy for inherited enzyme deficiency–macrophage-targeted glucocerebrosidase for Gaucher’s disease. N Engl J Med 324(21):1464–1470PubMedCrossRefGoogle Scholar
  7. Boot RG, Renkema GH, Verhoek M et al (1998) The human chitotriosidase gene. Nature of inherited enzyme deficiency. J Biol Chem 273(40):25680–25685PubMedCrossRefGoogle Scholar
  8. Boot RG, Verhoek M, de Fost M et al (2004) Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 103(1):33–39PubMedCrossRefGoogle Scholar
  9. Boot RG, Hollak CE, Verhoek M, Alberts C, Jonkers RE, Aerts JM (2010) Plasma chitotriosidase and CCL18 as surrogate markers for granulomatous macrophages in sarcoidosis. Clin Chim Acta 411(1–2):31–36PubMedCrossRefGoogle Scholar
  10. Bussink AP, Speijer D, Aerts JM, Boot RG (2007) Evolution of mammalian chitinase(−like) members of family 18 glycosyl hydrolases. Genetics 177(2):959–970PubMedCrossRefPubMedCentralGoogle Scholar
  11. Bussink AP, Verhoek M, Vreede J et al (2009) Common G102S polymorphism in chitotriosidase differentially affects activity towards 4-methylumbelliferyl substrates. FEBS J 276(19):5678–5688PubMedCrossRefGoogle Scholar
  12. Czartoryska B, Tylki-Szymanska A, Lugowska A (2000) Changes in serum chitotriosidase activity with cessation of replacement enzyme (cerebrosidase) administration in Gaucher disease. Clin Biochem 33(2):147–149PubMedCrossRefGoogle Scholar
  13. de Fost M, Hollak CE, Groener JE et al (2006a) Superior effects of high-dose enzyme replacement therapy in type 1 Gaucher disease on bone marrow involvement and chitotriosidase levels: a 2-center retrospective analysis. Blood 108(3):830–835PubMedCrossRefGoogle Scholar
  14. de Fost M, vom Dahl S, Weverling GJ (2006b) Increased incidence of cancer in adult Gaucher disease in Western Europe. Blood Cells Mol Dis 36(1):53–58PubMedCrossRefGoogle Scholar
  15. de Fost M, Out TA, de Wilde FA et al (2008a) Immunoglobulin and free light chain abnormalities in Gaucher disease type I: data from an adult cohort of 63 patients and review of the literature. Ann Hematol 87(6):439–449PubMedCrossRefPubMedCentralGoogle Scholar
  16. de Fost M, van Noesel CJ, Aerts JM, Maas M, Poll RG, Hollak CE (2008b) Persistent bone disease in adult type 1 Gaucher disease despite increasing doses of enzyme replacement therapy. Haematologica 93(7):1119–1120PubMedCrossRefGoogle Scholar
  17. Deegan PB, Moran MT, McFarlane I et al (2005) Clinical evaluation of chemokine and enzymatic biomarkers of Gaucher disease. Blood Cells Mol Dis 35(2):259–267PubMedCrossRefGoogle Scholar
  18. Deegan PB, Pavlova E, Tindall J et al (2011) Osseous manifestations of adult Gaucher disease in the era of enzyme replacement therapy. Medicine (Baltimore) 90(1):52–60CrossRefGoogle Scholar
  19. Dekker N, van Dussen L, Hollak CE et al (2011) Elevated plasma glucosylsphingosine in Gaucher disease: relation to phenotype, storage cell markers, and therapeutic response. Blood 118(16):e118–e127PubMedCrossRefPubMedCentralGoogle Scholar
  20. den Bakker MA, Grunberg K, Boonstra A, van Hal PT, Hollak CE (2012) Pulmonary arterial hypertension with plexogenic arteriopathy in enzyme-substituted Gaucher disease. Histopathology 61(2):324–326CrossRefGoogle Scholar
  21. Erjavec Z, Hollak CE, de Vries EG (1999) Hepatocellular carcinoma in a patient with Gaucher disease on enzyme supplementation therapy. Ann Oncol 10(2):243PubMedCrossRefGoogle Scholar
  22. Giraldo P, Irun P, Alfonso P et al (2011) Evaluation of Spanish Gaucher disease patients after a 6-month imiglucerase shortage. Blood Cells Mol Dis 46(1):115–118PubMedCrossRefGoogle Scholar
  23. Goldblatt J, Fletcher JM, McGill J, Szer J, Wilson M (2010) Enzyme replacement therapy “drug holiday”: Results from an unexpected shortage of an orphan drug supply in Australia. Blood Cells Mol Dis 46:107–110PubMedCrossRefGoogle Scholar
  24. Grabowski GA, Petsko GA, Kolodny EH (2010) Gaucher disease. McGraw-Hill, New York Google Scholar
  25. Hollak CE, van Weely S, van Oers MH, Aerts JM (1994) Marked elevation of plasma chitotriosidase activity. A novel hallmark of Gaucher disease. J Clin Invest 93(3):1288–1292PubMedCrossRefPubMedCentralGoogle Scholar
  26. Hollak C, Maas M, Akkerman E, den Heeten A, Aerts H (2001) Dixon quantitative chemical shift imaging is a sensitive tool for the evaluation of bone marrow responses to individualized doses of enzyme supplementation therapy in type 1 Gaucher disease. Blood Cells Mol Dis 27(6):1005–1012PubMedCrossRefGoogle Scholar
  27. Hollak CE, de Fost M, van Dussen L, vom Dahl S, Aerts JMFG (2009) Enzyme therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose–response relationships. Expert Opin Pharmacother doi: 10.1517/14656560903270520Google Scholar
  28. Kuter DJ, Mehta A, Hollak CE et al (2013) Miglustat therapy in type 1 Gaucher disease: clinical and safety outcomes in a multicenter retrospective cohort study. Blood Cells Mol Dis 51(2):116–124PubMedCrossRefGoogle Scholar
  29. Maas M, Hollak CE, Akkerman EM, Aerts JM, Stoker J, den Heeten GJ (2002) Quantification of skeletal involvement in adults with type I Gaucher’s disease: fat fraction measured by Dixon quantitative chemical shift imaging as a valid parameter. AJR Am J Roentgenol 179(4):961–965PubMedCrossRefGoogle Scholar
  30. Mistry PK, Sirrs S, Chan A et al (2002) Pulmonary hypertension in type 1 Gaucher’s disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab 77(1–2):91–98PubMedCrossRefGoogle Scholar
  31. Neudorfer O, Giladi N, Elstein D et al (1996) Occurrence of Parkinson’s syndrome in type I Gaucher disease. QJM 89(9):691–694PubMedCrossRefGoogle Scholar
  32. Pavlova EV, Deegan PB, Tindall J et al (2011) Potential biomarkers of osteonecrosis in Gaucher disease. Blood Cells Mol Dis 46(1):27–33PubMedCrossRefGoogle Scholar
  33. Poll LW, Koch JA, Willers R et al (2002) Correlation of bone marrow response with hematological, biochemical, and visceral responses to enzyme replacement therapy of nonneuronopathic (type 1) Gaucher disease in 30 adult patients. Blood Cells Mol Dis 28(2):209–220PubMedCrossRefGoogle Scholar
  34. Roberts WC, Fredrickson DS (1967) Gaucher’s disease of the lung causing severe pulmonary hypertension with associated acute recurrent pericarditis. Circulation 35(4):783–789PubMedCrossRefGoogle Scholar
  35. Roca M, Mota J, Alfonso P, Pocovi M, Giraldo P (2007) S-MRI score: A simple method for assessing bone marrow involvement in Gaucher disease. Eur J Radiol 62(1):132–137PubMedCrossRefGoogle Scholar
  36. Rosenthal DI, Doppelt SH, Mankin HJ et al (1995) Enzyme replacement therapy for Gaucher disease: skeletal responses to macrophage-targeted glucocerebrosidase. Pediatrics 96(4 Pt 1):629–637PubMedGoogle Scholar
  37. Schoonhoven A, Rudensky B, Elstein D et al (2007) Monitoring of Gaucher patients with a novel chitotriosidase assay. Clin Chim Acta 381(2):136–139PubMedCrossRefGoogle Scholar
  38. Shiran A, Brenner B, Laor A, Tatarsky I (1993) Increased risk of cancer in patients with Gaucher disease. Cancer 72(1):219–224PubMedCrossRefGoogle Scholar
  39. Sirrs S, Casey R, Patterson MA, McNeil C, Paquin W, Amato D (2013) Variation in chitotriosidase values measured on simultaneous samples by two commercial laboratories. Am J Hematol 88(11):980PubMedCrossRefGoogle Scholar
  40. Tayebi N, Callahan M, Madike V et al (2001) Gaucher disease and parkinsonism: a phenotypic and genotypic characterization. Mol Genet Metab 73(4):313–321PubMedCrossRefGoogle Scholar
  41. van Dussen L, Lips P, Everts VE et al (2011) Markers of bone turnover in Gaucher disease: modeling the evolution of bone disease. J Clin Endocrinol Metab 96(7):2194–2205PubMedCrossRefGoogle Scholar
  42. van Dussen L, Cox TM, Hendriks EJ et al (2012) Effects of switching from a reduced dose imiglucerase to velaglucerase in type 1 Gaucher disease: clinical and biochemical outcomes. Haematologica 97(12):1850–1854PubMedCrossRefPubMedCentralGoogle Scholar
  43. van Eijk M, van Roomen CP, Renkema GH et al (2005) Characterization of human phagocyte-derived chitotriosidase, a component of innate immunity. Int Immunol 17(11):1505–1512PubMedCrossRefGoogle Scholar
  44. Xu R, Mistry P, McKenna G et al (2005) Hepatocellular carcinoma in type 1 Gaucher disease: a case report with review of the literature. Semin Liver Dis 25(2):226–229PubMedCrossRefGoogle Scholar
  45. Young E, Chatterton C, Vellodi A, Winchester B (1997) Plasma chitotriosidase activity in Gaucher disease patients who have been treated either by bone marrow transplantation or by enzyme replacement therapy with alglucerase. J Inherit Metab Dis 20(4):595–602PubMedCrossRefGoogle Scholar
  46. Zimran A, Altarescu G, Elstein D (2010) Nonprecipitous changes upon withdrawal from imiglucerase for Gaucher disease because of a shortage in supply. Blood Cells Mol Dis 46:111–114PubMedCrossRefGoogle Scholar

Copyright information

© SSIEM and Springer Science+Business Media Dordrecht 2014

Authors and Affiliations

  • L. van Dussen
    • 1
  • E. J. Hendriks
    • 2
  • J. E. M. Groener
    • 2
  • R. G. Boot
    • 2
  • C. E. M. Hollak
    • 1
  • J. M. F. G. Aerts
    • 2
  1. 1.Department of Endocrinology and Metabolism, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands
  2. 2.Department of Medical Biochemistry, Academic Medical CenterUniversity of AmsterdamAmsterdamThe Netherlands

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