Macrophage Surrogate Biomarkers

Of the many avenues attempted in the various common and less common lysosomal storage diseases, none is a completely satisfactory biomarker. This is a distinct disadvantage when the alternative may be invasive procedures that are more dangerous than merited by the status of the patient. A class of biomarkers has been incorporated into the evaluation initially of Gaucher disease, but now also of Fabry disease and type B Niemann-Pick disease, which are surrogate in the sense that they measure plasma levels of macrophage lipid or chemokines. Examples of this class are chitotriosidase and C-C chemokine ligand 18 (CCL 18; also called pulmonary and activation-regulated chemokine, PARC) that can be measured in plasma and in urine. Chitotriosidase in Gaucher disease [39] was considered a specific marker of disease severity and then as a measure of response to therapy [40]. Among the methodological issues with using chitotriosidase is that it is genetically deficient in 6% of all persons, and genotyping should be done. The surrogate marker CCL18/PARC was then introduced [41] because it had the advantage of being present in everyone, yet it is not nearly as elevated in patients with Gaucher disease relative to healthy individuals. An advantage of CCL18/PARC over chitotriosi-dase assays is the less difficult assay of CCL18/PARC. In male patients with Fabry disease, chitotriosidase levels were found to be significantly elevated but were not correlated with disease severity, although in some cases may have normalized with therapy [42]. In two siblings with type B Niemann-Pick disease, there were elevated levels of both markers, but not commensurate with clinical severity [43]. Recently, urinary levels of chitotriosidase and CCL 18/PARC have been measured in Gaucher disease, but they do not appear to correlate with plasma levels, although there was correlation after exposure to treatment [44]. Interestingly, despite its indirect relationship to disease-specific parameters, the popularity of chitotriosidase as a putative biomarker has led to its use in testing other nonspecific markers [45] . This should not, of course, be the intention of biomarkers (i.e., that they correlate with each other) because then one is caught up in loops of correlation not one of which is related directly to a disease-specific parameter.

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Project Management Made Easy

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