Gaucher Disease

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Laboratory features

Glucocerebrosidase is the lysosomal hydrolase responsible for the degradation of the natural glycosphingolipid, glucosylceramide (glucocerebroside), into ceramide and glucose. Deficiency of this enzyme results in the accumulation of undegraded glucosylceramide, almost exclusively in macrophages. The glucosylceramide concentration in the spleen can be increased 10- to 1000-fold, but high levels are also detected in liver and bone marrow specimens. In contrast, the plasma concentration of glucosylceramide is only moderately increased, on average approximately two-fold.

Significant decreases or downward trends in glucosylceramide concentrations in response to enzyme therapy have been noted in patients with various Gaucher disease phenotypes. Apart from glycolipid levels, a considerable number of other measurements change. Abnormalities in the levels of other proteins, including acid hydrolases and lipids, have been observed in the tissues and plasma of Gaucher patients. Several of these abnormalities are of interest because of their potential role in the pathophysiology of the disease, their ability to serve as markers for disease severity, and their application in measuring the efficacy of therapeutic intervention. One of the earliest examples is the elevated plasma concentration of tartrate-resistant acid phosphatase 5B (TRAP), which is secreted by the Gaucher macrophages. Other plasma abnormalities frequently used to monitor disease progression and response to therapy are ferritin, angiotensin-converting enzyme (ACE), hexosaminidase, and the lysosomal hydrolase, chitotriosidase.

The latter has been discovered by AMC researchers and is by far the most highly elevated enzyme in symptomatic patients. In clinically affected individuals, chitotriosidase levels are elevated at least 100-fold, but may be higher than 600 times the median value detected in healthy volunteers [1]. The function of chitotriosidase is as yet unknown, but its close resemblance to the non-vertebrate chitinases, which act in the defence against or degradation of chitin-containing pathogens, such as fungi, may provide a clue to its biological role in humans. Extensive studies have revealed that chitotriosidase originates from the Gaucher cell and has a close relationship with the body burden of Gaucher cells. It can thus be used in addition to other parameters of disease activity to monitor disease progression and response to therapy. However, one has to bear in mind that 6% of the entire population, including Gaucher patients, have a complete lack of plasma chitotriosidase activity due to a single mutation in the chitotriosidase gene [2]. The carrier prevalence for this mutation can be as high as 40%, resulting in lower levels of chitotriosidase activity. CCL18/PARC is a chemokine secreted by Gaucher cells as well and can be used as a reliable alternative, although elevations are not as striking as found for chitotriosidase. More recent studies revealed elevations in MIP1beta. This cytokine is thought to play a role in bone remodelling and may therefore be a better marker for ongoing bone disease symptomatology. Several other plasma abnormalities described in Gaucher disease may contribute to the clinical picture, including reduced lipoprotein levels, hypergammaglobulinaemia, and elevated levels of proinflammatory cytokines and macrophage-activation markers.


[1] 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: 1288-92.

[2] Boot RG, Renkema GH, Strijland A, et al. Cloning of a cDNA encoding chitotriosidase, a human chitinase produced by macrophages. J Biol Chem 1995; 270: 26252-6.


Marieke Biegstraaten

Department of Internal Medicine, Division of Endocrinology and Metabolism, F5-169
Academic Medical Center, University of Amsterdam
PO box 22700
1100 DE Amsterdam, the Netherlands

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