Identification and use of biomarkers in Gaucher disease and other lysosomal storage diseases

The value of biomarkers in the clinical management of lysosomal storage diseases is best illustrated by the present use of plasma chitotriosidase levels in the diagnosis and monitoring of Gaucher disease. The enzyme chitotriosidase is specifically produced and secreted by the pathological storage macrophages (Gaucher cells). Plasma chitotriosidase levels are elevated on average 1000-fold in symptomatic patients with Gaucher disease and reflect the body burden on storage cells. Changes in plasma chitotriosidase reflect changes in clinical symptoms. Monitoring of plasma chitotriosidase levels is nowadays commonly used in decision making regarding initiation and optimization of costly therapeutic interventions (enzyme replacement therapy or substrate reduction therapy). A novel substrate has been developed that further facilitates the measurement of chitotriosidase in plasma samples. Moreover, an alternative Gaucher-cell marker, CCL18, has been very recently identified and can also be employed to monitor the disease, particularly in those patients lacking chitotriosidase due to a genetic mutation. There is a need for comparable surrogate markers for other lysosomal storage diseases and the search for such molecules is an area of intense investigation.
Conclusion: The use of biomarkers can provide valuable insight into the molecular pathogenesis of LSDs, such as Gaucher disease and Fabry disease.     

Expression profiling reveals alternative macrophage activation and impaired osteogenesis in periprosthetic osteolysis

Interactions between periprosthetic cells and prosthetic wear debris have been recognized as an important event in the development of osteolysis and aseptic loosening. Although the ability of wear debris to activate pro‐inflammatory macrophage signaling has been documented, the full repertoire of macrophage responses to wear particles has not been established. Here, we examined the involvement of alternative macrophage activation and defective osteogenic signaling in osteolysis. Using real‐time RT‐PCR analysis of periprosthetic soft tissue from osteolysis patients, we detected elevated levels of expression of alternative macrophage activation markers (CHIT1, CCL18), chemokines (IL8, MIP1 α) and markers of osteoclast precursor cell differentiation and multinucleation (Cathepsin K, TRAP, DC‐STAMP) relative to osteoarthritis controls. The presence of cathepsin K positive multinuclear cells was confirmed by immunohistochemistry. Reduced expression levels of the osteogenic signaling components BMP4 and FGF18 were detected. Expression levels of TNF‐α, IL‐6, and RANKL were unchanged, while the anti‐osteoclastogenic cytokine OPG was reduced in osteolysis patients, resulting in elevated RANKL:OPG ratios. In vitro studies confirmed the role of particulate debris in alternative macrophage activation and inhibition of osteogenic signaling. Taken together, these results suggest involvement in osteolysis of alternative macrophage activation, accompanied by elevated levels of various chemokines. Increased recruitment and maturation of osteoclast precursors is also observed, as is reduced osteogenesis. These findings provide new insights into the molecular pathogenesis of osteolysis, and identify new potential candidate markers for disease progression and therapeutic targeting. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:106–116, 2008     

冠心病患者血中壳三糖苷酶活性的研究

目的研究冠心病患者血清壳三糖苷酶活性的临床意义。方法测定126例冠心病患者血清壳三糖苷酶的活性及其血脂水平,并与对照组相比较,分析其临床意义。结果在对照组、稳定性冠心病(SCHD)组和急性冠脉综合征(ACS)组壳三糖苷酶活性(nm o l/m l.h)分别为76.2±24.6,85.2±25.7,102.3±26.2。冠心病组显著高于对照组(分别为P<0.05、P<0.01),同时ACS组与SCHD组也存在显著差异(P<0.01)。结论壳三糖苷酶可以作为体内巨噬细胞激活的标志,反映动脉硬化症患者巨噬细胞的功能,检测其血清含量可能有助于稳定型心绞痛与不稳定型心绞痛的鉴别诊断。     

Association of chitotriosidase genotype with the development of non‐alcoholic fatty liver disease

Aim: Based on the role of chitotriosidase (CHIT‐1) in the evolution of non‐alcoholic fatty liver disease, we explored whether CHIT‐1 mutant allele plays a role in NAFLD progression. Methods: We genotyped 200 patients with NAFLD (110 with non‐alcoholic steatohepatitis [NASH] and 90 with simple steatosis) and 100 control subjects. The χ²‐test was performed for a case–control study. Odds ratios (OR) were adjusted for age, sex and body mass index (BMI) by using multiple logistic regression analysis with genotypes (additive model), age, sex and BMI as the independent variables. Multiple linear regression analysis was performed to test the independent effect of risk allele on clinical parameters while considering the effects of other variables (age, sex and BMI), which were assumed to be independent of the effect of the single nucleotide polymorphism. Results: The risk allele frequency of CHIT‐1 wild type (Wt) was 0.71 in the control subjects, 0.77 in simple steatosis and 0.92 in patients with NASH. The OR (95% confidence interval) adjusted for age and BMI was 1.73. Multiple linear regression analysis indicated that the CHIT‐1 Wt was significantly associated with increases in ferritin levels (P = 0.014) and the fibrosis stage (P = 0.011) in the patients with NASH, even after adjustment for age, sex and BMI, corroborating that the presence of the CHIT‐1 Wt allele was an independent predictor of fibrotic NAFLD. In contrast, the steatosis grade was not associated with CHIT‐1 mutant allele. Conclusion: These findings suggest that a functional polymorphism in the CHIT‐1 gene protects against NAFLD progression.     

New aspects of liver abnormalities as part of the systemic mast cell activation syndrome

Background/Aims: This study was aimed at investigating the form and prevalence of liver involvement in patients with systemic mast cell activation syndrome, a possibly common subvariant of systemic mastocytosis. An attempt was made to shed light on potential mechanisms responsible for mast cell mediator‐related liver abnormalities. Methods: The methods used were clinical investigation, biochemical determination of cholesterol, transaminases and bilirubin in blood, determination of chitotriosidase by enzyme‐linked immunosorbent assay technique, and quantitative reverse transcribed‐polymerase chain reaction to determine chitotriosidase expression. Results: An elevation of plasma cholesterol was detected in 75% of the patients; elevations of transaminases and bilirubin were determined in 40 and 36% of the patients respectively; hepatomegaly or morphological hepatic alterations were observed in 34%. Chitotriosidase level in blood as a surrogate parameter for Kupffer cell activation in the liver was unchanged. However, chitotriosidase expression in isolated mast cells was downregulated at the mRNA level. Conclusions: Hypercholesterolaemia and liver abnormalities are frequently found in patients with the mast cell activation syndrome. Hence, the mast cell activation syndrome should be considered at an early stage as a possible cause of hypercholesterolaemia and of hepatic abnormalities of unknown reason. Mast cell activation may be indicated by a reduced expression of the enzyme chitotriosidase in blood‐derived mast cells as well as by an increased plasma cholesterol level.     

不同类型糖尿病视网膜病变患者血清和肽素和几丁质酶1水平的变化及影响因素

目的　探讨不同类型糖尿病视网膜病变（diabetic retinopathy,DR）患者血清和肽素和几丁质酶1（Chitotriosidase,CHIT1）水平的变化,并分析其影响因素。方法　选取2型糖尿病患者197例作为研究对象,将患者分为:无糖尿病视网膜病变（non-diabetic retinopathy,NDR）组、非增生型糖尿病视网膜病变（non-proliferative diabetic retinopathy,NPDR）组、增生型糖尿病视网膜病变（proliferative diabetic retinopathy,PDR）组;另选取同期在我院进行体检的健康体检者60人作为正常对照（normal control,NC）组。收集所有受试者的一般资料,抽取受试者晨起空腹静脉血5 mL,检测总胆固醇、甘油三酯、谷草转氨酶、谷丙转氨酶、血肌酐及空腹血糖（fasting plasma glucose,FPG）、糖化血红蛋白（hemoglobin Alc,HbA1c）、空腹胰岛素（fasting plasma insulin,FINS）水平,用稳态模型评估法计算胰岛素抵抗指数（homeostasis model assessment for insulin resistance,HOMA-IR）,计算肾小球滤过率。采用ELISA法测定血清和肽素和CHIT1含量。结果　NDR组、NPDR组、PDR组患者血清的和肽素、CHIT1含量均高于NC组,且随着DR病情进展逐渐升高,差异均有统计学意义（均为P＜0.05）;与NC组相比,NDR组、NPDR组、PDR组患者的FPG、HbA1c、HOMA-IR水平均依次升高,PDR组最高,差异均有统计学意义（均为P＜0.05）;各组受试者的总胆固醇、甘油三酯、谷草转氨酶、谷丙转氨酶、血肌酐、肾小球滤过率、FINS水平组间比较,差异均无统计学意义（均为P＞0.05）。Pearson相关性分析结果显示:血清和肽素含量与年龄、DM病程、SBP、FPG、HbA1c、HOMA-IR、CHIT1含量均呈正相关（r分别为0.11、0.75、0.52、0.83、0.88、0.58、0.96,均为P＜0.05）;血清CHIT1含量与年龄、DM病程、SBP、DBP、FPG、HbA1c、FINS、HOMA-IR、和肽素含量呈正相关（r分别为0.12、0.77、0.48、0.12、0.84、0.88、0.14、0.61、0.96,均为P＜0.05）。多元线性逐步回归分析结果显示:HbA1c、SBP、FPG是血清和肽素含量的独立影响因素,HbA1c、FPG、DM病程、HOMA-IR是血清CHIT1含量的独立影响因素。结论　DR患者的和肽素和CHIT1水平显著升高,且与DR的程度相关,二者可能共同参与了DR的发生发展。     

Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis

Verbeek MM, Notting EA, Faas B, Claessens‐Linskens R, Jongen PJH. Increased cerebrospinal fluid chitotriosidase index in patients with multiple sclerosis.
Acta Neurol Scand: 2010: 121: 309–314.
© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard. Objective – To investigate chitotriosidase (CTTS) activity in serum and cerebrospinal fluid (CSF) in multiple sclerosis (MS) patients in relation to disease course and CSF markers for immune activation or inflammation. Materials and methods – We studied 80 patients with relapsing–remitting MS (RRMS), 24 with secondary progressive MS (SPMS), 20 with primary progressive MS (PPMS) and 29 patients with other neurological disorders (OND). We measured CTTS activity and studied the correlation with CSF mononuclear cell count (MNC) and intrathecal IgG production. Results – CTTS activity was significantly higher in CSF, but not in serum, from the total MS group compared with OND and controls. In RRMS and SPMS CTTS, index was increased compared with controls (RRMS, 0.10 ± 0.21; SPMS, 0.10 ± 0.15; controls, 0.021 ± 0.020), but not in PPMS (0.061 ± 0.052). CTTS index was higher in MS patients with elevated MNC or CSF‐restricted oligoclonal IgG bands than in MS patients without these CSF findings. Conclusions – CTTS index is elevated in RRMS and SPMS. The CTTS index is related to CSF markers of inflammation or immune activation.     

Primary Lateral Sclerosis: Clinical,radiological and molecular features

Primary Lateral Sclerosis (PLS) is an uncommon motor neuron disorder. Despite the well-recognisable constellation of clinical manifestations, the initial diagnosis can be challenging and therapeutic options are currently limited. There have been no recent clinical trials of disease-modifying therapies dedicated to this patient cohort and awareness of recent research developments is limited. The recent consensus diagnostic criteria introduced the category ‘probable’ PLS which is likely to curtail the diagnostic journey of patients. Extra-motor clinical manifestations are increasingly recognised, challenging the view of PLS as a 'pure' upper motor neuron condition. The post mortem literature of PLS has been expanded by seminal TDP-43 reports and recent PLS studies increasingly avail of meticulous genetic profiling. Research in PLS has gained unprecedented momentum in recent years generating novel academic insights, which may have important clinical ramifications.