Background: Gaucher disease (GD) is a rare autosomal recessive genetic disorder resulting from mutations in the GBA1 gene located on chromosome 1 (1q21), which codes for the lysosomal enzyme glucocerebrosidase (GCase or glucosylceramidase or acid β-glucosidase 1). Within lysosomes, this enzyme plays a crucial role in the hydrolysis of glucosylceramide into ceramide and glucose; when its catalytic activity is impaired, there is an accumulation of glucosylceramide in macrophages, which transform into the Gaucher cells characteristic of the disease. These cells can infiltrate the bone marrow, liver, spleen, and other organs, causing the characteristic symptoms of the pathology. Growth Differentiation Factor 15 (GDF-15) is a divergent member of the TGF-β superfamily and has diverse pathophysiological roles in cancers, cardiometabolic disorders, mitochondrial diseases and other diseases. GDF-15 controls hematopoietic growth, energy homeostasis, adipose tissue metabolism, body growth, bone remodeling, and response to stress signals. Elevated circulating levels of GDF-15 have been reported in patients with inborn errors of metabolism such as mitochondrial diseases, while in the case of non-mitochondrial diseases such as GD the reports are limited. In this context, we aimed to investigate the clinical significance of circulating GDF-15 levels in patients with GD, and to explore possible correlations with disease activity, spleen and liver volume, bone deformities as well as genotype.

Patients and Methods: Thirty adult patients with GD under enzyme replacement therapy were included in the study, while 20 apparently healthy individuals matched for sex and age were served as controls. Along with measurements of specific hematologic and blood chemistry parameters related to GD, GDF-15 levels were measured using the electrochemiluminescence Roche Cobas e411 immunoassay automated analyzer (Roche Diagnostics, Rotkreuz, CH). Results expressed as Mean±SEM, while to linearize correlation models log transformations were used when appropriate.

Results: We found that: a) GDF-15 levels were significantly higher in patients with GD 3,147±1,316ng/mL (ranged from 390.0-18,381.0ng/mL) compared controls 665.0±50.9ng/mL (ranged from 269.6-1,129.0ng/mL), p<0.001, and they were independent of patients' age (p>0.106); b) GDF-15 levels were significantly correlated with Hb r=-0.534, p=0.02, PLT r=-0.602, p=0.008, RDW r=0.805, p<0.001, Fe r=-0.744, p<0.001 and ferritin r=0.617, p=0.006, independently of low grade inflammation and WBC; c) Higher GDF-15 levels were associated with lower total and HDL-cholesterol concentrations (p<0.01); d) GDF-15 levels were significantly correlated with chitotriosidase activity r=0.606, p<0.001, spleen volume r=0.633, p=0.009, and Bone Mineral Density measurements for L1-L4 vertebrae r= -0.581, p<0.01 and e) GDF-15 levels decreased slowly with enzyme replacement therapy r=-0.461, p=0.053, slope -0.060 whereas chitotriosidase activity r=-0.649, p=0.004, slope -2.3 and ferritin levels r=-0.730, p<0.001, slope -1.8, decreased more abrubtly..

Conclusions: To our knowledge this the first study, which demonstrates a significant multifactorial role of GDF-15 cytokine in patients with GD, as its levels correlated significantly with clinical and laboratory features of the disease. These findings support the emerging role of GDF-15 in GD, but should be confirmed by further large-scale longitudinal studies before being integrated in patients with GD follow-up.

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2025
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