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|D-dimères et atteintes osseuses et pulmonaires dans la maladie de Gaucher||Dans la maladie de Gaucher, les atteintes osseuses et pulmonaires constituent 2 causes majeures de morbidité. Pour évaluer le caractère prédictif potentiel du taux de D-dimères (indicateur fiable d’une thrombose microvasculaire active), une étude égyptienne a inclus 56 patients présentant une maladie de Gaucher (36 types 1 et 20 types 3) et 30 témoins bien portants. Le taux de D-dimères était significativement plus élevé chez tous les patients par rapport aux témoins et chez les patients avec une maladie de type 3 par rapport aux patients avec une maladie de type 1. Une proportion plus importante de patients avec un type 3 présentait une atteinte pulmonaire et une proportion plus importante de patients avec un type 1 présentait une atteinte osseuse. Le taux de D-dimères était significativement plus élevé en cas d’anomalies des os longs à l’IRM et en cas d’aspect en verre dépoli au scanner thoracique. Les patients splénectomisés présentaient un taux plus élevés de D-dimères que ceux qui ne l’étaient pas. Selon les auteurs ces résultats montrent que le taux de D-dimères est significativement élevé dans la maladie de Gaucher, en particulier dans le type 3, et suggèrent qu’il représente un marqueur prédictif potentiel d’atteinte des os et des poumons utilisable au cours de la surveillance de la réponse au traitement.|
D-dimer assay in Egyptian patients with Gaucher disease: correlation with bone and lung involvement
Sherif, Eman Ma; Tantawy, Azza AGa; Adly, Amira AMa; Kader, Hossam Ab; Ismail, Eman ARc
aDepartment of Pediatrics, Egypt, bDepartment of Radiology, Egypt, cDepartment of Clinical Pathology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
Received 20 August, 2010, Revised 17 October, 2010, Accepted 27 October, 2010
Correspondence to Eman A.R. Ismail, MD, 5 Nageb Mahfoz Street, Agouza, 12654 Giza, Egypt Fax: +202 3337 5435; e-mail: firstname.lastname@example.org
Gaucher disease is the most frequent lysosomal storage disorder. Bone and lung involvement are two major causes of morbidity in this disease. D-dimer is a reliable indicator of active microvascular thrombosis, even in patients without overt hypercoagulation. This study aimed to assess D-dimer levels in Gaucher disease, correlating this marker to clinical characteristics and radiological parameters to investigate its role as a potential predictor for the occurrence and severity of skeletal and pulmonary manifestations. The study population consisted of 56 Egyptian patients with Gaucher disease, 36 had type 1 Gaucher disease (64.3%) and 20 had type 3 Gaucher disease (35.7%). Thirty healthy individuals were enrolled as a control group. D-dimer levels were significantly higher in all patients with Gaucher disease compared with controls (P < 0.001). Patients with type 3 showed significantly higher D-dimer concentrations compared with type 1 (P < 0.001). Pulmonary involvement was present in a significant proportion among type 3 Gaucher patients (P < 0.05), whereas bone changes were present in a higher percentage in type 1 compared with type 3 Gaucher patients. D-dimers were significantly higher in patients with abnormal MRI findings of the long bones and in those with ground glass appearance on high-resolution computerized tomography of the chest compared with patients with normal radiology (P < 0.001). Splenectomized patients displayed significantly higher D-dimer levels compared with nonsplenectomized patients (P < 0.001). Our results suggest that D-dimer is significantly elevated in Gaucher disease, particularly type 3, and may be considered as a potential marker of risk prediction of bone and lung involvement that could be used to monitor treatment response.
The lysosomal storage diseases have a cumulative incidence of 1 in 5000 live births . Gaucher disease predominates among this group, having a frequency of 1 in 40 000 in the United States [2,3]. Gaucher disease results from an autosomal recessive deficiency of the lysosomal enzyme acid [beta]-glucosidase [glucocerebrosidase (GBA)], which is responsible for hydrolysis of glucocerebroside [glucosylceramide (GLC)] . Mutations in the GBA gene result in Gaucher disease and many of these mutations are missense alterations that may cause misfolding, decreased stability and/or mistrafficking of this lysosomal protein . Absent or reduced enzymatic activity leads to accumulation of GLC in various cells of the macrophage–monocyte system (Gaucher cells) [6,7]. Classically, the pathophysiology of Gaucher disease has been attributed to the amount, location and rate of accumulation of the stored material [8,9]. The manifestations of Gaucher disease occurring due to accumulation of Gaucher cells in three main anatomical compartments, namely the osseous skeleton, the bone marrow and visceral organs [4,10].
As with most genetic diseases, the signs and symptoms of Gaucher disease present along a continuum, ranging from the lethal neonatal form to the asymptomatic form . Currently, Gaucher disease is classified into three clinical forms: nonneuropathic (type 1), acute neuropathic (type 2) and chronic neuropathic (type 3) [3,10]. Patients with type 1 disease may present at any age with hepatosplenomegaly, anemia, thrombocytopenia, often skeletal involvement (such as avascular necrosis of the large joints or pathological fractures) or lung disease. Age and mode of presentation as well as the eventual clinical course are highly variable, yet phenotypic heterogeneity can be attributed only in part to specific mutations [9,12].
Bone disease usually designates the advanced stages of Gaucher disease, but susceptibility to fractures and avascular necrosis can be the first sign of Gaucher disease in otherwise asymptomatic patients . The skeletal aspects of the disease have a much greater impact on patients' quality of life than the hematological and visceral aspects. Moreover, skeletal manifestations are commonly seen in patients with normal hematology . Therefore, it is important for physicians not to focus only on hematological and visceral complications on the expense of skeletal involvement when assessing the response to enzyme replacement therapy (ERT) [15,16]. Nearly, all patients with Gaucher disease have radiological evidence of skeletal involvement including Erlenmeyer flask deformity, osteopenia, osteosclerosis, osteonecrosis, fractures and bone marrow infiltration. Skeletal involvement follows three basic processes: focal disease (irreversible lesions such as osteonecrosis and osteosclerosis), local disease (reversible abnormalities adjacent to heavily involved marrow such as cortical thinning and long bone deformity) and generalized osteopenia . For more accurate assessment of bone disease in adults and children, it is desirable to conduct MRI studies at centers with radiologists experienced in evaluating patients with Gaucher disease .
Symptomatic lung involvement may be common at presentation, and may progress over the course of the disease to pulmonary hypertension in some patients, particularly in type 3 Gaucher disease . Chest radiographs may demonstrate reticulonodular changes, and on high-resolution computerized tomography (HRCT), a range of abnormal patterns including widespread ground glass opacification may be present [19,20].
Many factors may trigger or aggravate symptoms and signs of the disease including environmental or acquired conditions, such as viral infections or pregnancy. In addition, other concurrent genetic defects such as partial deficiency of coagulation factors aggravate the tendency to bleeding and may contribute to the variability of clinical manifestations in Gaucher patients. These modifiers may be helpful in predicting risk of developing bone and/or lung disease [3,10,21]. A logical theory to explain the incidence of avascular bone necrosis and pulmonary hypertension in Gaucher disease was an inherited predilection for hypercoagulability [9,22]. Gaucher disease has been the playground to develop new therapeutic interventions such as ERT and substrate-reduction therapy. The availability of these costly therapies has stimulated research regarding suitable biomarkers to monitor onset and progression of disease, as well as the efficacy of therapeutic intervention .
D-dimer assays are ordered, along with laboratory tests that help to rule out, diagnose and monitor conditions associated with hypercoagulability [24,25]. The possibility of correlation between avascular bone necrosis and pulmonary hypertension in Gaucher patients with D-dimer levels was considered because it would implicate involvement of microthrombosis, without expecting a quantitative correlation with hypercoagulability per se . However, there have been few studies that evaluated the impact of this reliable indicator of coagulation on the development and severity of skeletal and pulmonary manifestations in Gaucher disease.
Therefore, this study aimed to assess D-dimer levels in Egyptian patients with Gaucher disease as a potential predictor for the occurrence and severity of bone and lung involvement correlating this marker to clinical characteristics and radiological parameters.
Patients and methods
This cross-sectional study was conducted on 56 consecutive patients with Gaucher disease attending the Hematology/Oncology Clinic in Pediatric Hospital, Ain Shams University, from June 2009 to May 2010. They were 33 men and 23 women, with a male to female ratio of 1.4: 1. The mean age at diagnosis in the study population as a whole was 6.0 ± 3.9 years (range, 2.5–13 years). Control samples (peripheral blood) were obtained from 30 healthy children and adolescents with no history of inborn errors of metabolism in their first-degree and second-degree relatives. Twelve were men and 18 were women (male to female ratio, 1: 1.5). The mean age of the control population was 7.4 ± 4.24 years (range, 3–15 years). A written consent was obtained from the guardian of each case and control before participation in the study. The study was approved from the local ethical committee.
All patients were subjected to full medical history with special emphasis on bone manifestations (pains or fractures), hematological manifestations (pallor, bleeding and history of blood transfusion), pulmonary manifestations (cough, dyspnea and recurrent chest infections) and neurological symptoms (squint, convulsions, bulber manifestations, trismus and manifestations suggestive of cerebellar affection). Thorough clinical examination was performed laying stress on anthropometric measures, abdominal examination with assessment of hepatic and splenic size and full neurological examination including cranial nerves, motor and sensory systems. Radiological investigations included plain radiograph on long bones, chest radiograph, abdominal ultrasonography to assess the volume of liver and spleen in cubic centimeter (calculated as multiples of normal sizes predicted for body weight)  and MRI on pelvis and femur, as well as HRCT on both lung fields.
Laboratory investigations for Gaucher patients included complete blood count, examination of peripheral blood-stained smears, bone marrow aspiration and examination of stained smears and coagulation profile, as well as liver and renal function tests. GBA enzyme activity was assessed in peripheral blood leukocytes and plasma chitotriosidase was measured at diagnosis and for follow-up of the response of ERT as a sensitive indicator of dose effects. Molecular analysis of the acid GBA gene was performed for 18 patients.
Diagnosis of Gaucher disease was based on the presence of hepatosplenomegaly, bone involvement, hematological manifestations and developmental delay with or without neurological manifestations in the form of occulomotor abnormalities and/or convulsions. This was confirmed by laboratory findings of Gaucher cells in bone marrow aspirate and biopsy, low GBA activity  and high plasma level of chitotriosidase activity [26,27].
The clinical and laboratory characteristics of the studied Gaucher patients are summarized in Table 1. The studied patients were divided into two groups:
Table 1 Clinicopathological characteristics of the studied Gaucher patients
Group I included 36 patients with type 1 Gaucher disease (64.3%). They were 20 men and 16 women with a male to female ratio of 1.3: 1. Their ages at the time of the study ranged from 2.5 to 18 years with a mean of 6.6 ± 5.7 years. Type 1 patients presented initially with hepatosplenomegaly, bony manifestations, anemia and thrombocytopenia. At time of the study, 19 of 36 type 1 patients had anemia and 15 had thrombocytopenia as well as organomegaly. The duration of treatment ranged from 1 to 8 years with a mean of 2.9 ± 2.4 years. They were under ERT in a dose ranging from 60 to 90 U/kg per 2 weeks with a mean of 66 ± 13.4 U/kg per 2 weeks.
Group II included 20 patients with type 3 Gaucher disease (35.7%). They were 12 men and eight women (male to female ratio, 1.5: 1). Their ages at the time of the study ranged from 2.5 to 15 years with a mean of 7.8 ± 4.4 years. Type 3 patients presented with neurological manifestations in the form of ophthalmoplegia, neck stiffness, dysphagia, convulsions and trismus, in addition to visceral and hematological manifestations. The duration of treatment ranged from 1.5 to 8 years with a mean of 6.6 ± 5.7 years. They were under ERT in a dose ranging from 60 to 120 U/kg per 2 weeks with a mean of 84 ± 20.8 U/kg per 2 weeks.
None of the studied patients had advanced liver disease, active inflammatory conditions or were on anticoagulant therapy at time of study. Fourteen patients (35%) were splenectomized prior to the onset of ERT. All patients were under regular ERT [28,29] for a period of 1–8 years starting from January 1999. ERT was first given using the placenta-derived aglucerase (Ceredase; Genzyme Corporation, Cambridge, Massachusetts, USA) at low dose regimen (15 U/kg per 2 weeks). The recombinant enzyme imiglucerase (Cerezyme; Genzyme Corporation) was applied in March 1999 in a dose of 20–30 U/kg per month, divided into four equal weekly doses. In July 1999, Cerezyme was administered in a dose of 60 U/kg per 2 weeks. Six patients with type 3 received high doses of 120 U/kg per 2 weeks, one of them had progressive neurological disease and the others suffered severe pulmonary involvement.
Blood sampling and assay of d-dimer
As part for routine work-up for Gaucher disease, peripheral blood samples were collected on 3.2% buffered sodium citrate at a ratio of nine parts blood to one part anticoagulant (1: 10 ratio) and centrifuged at 1600 g for 15 min. D-dimer concentrations were determined in platelet-poor plasma using Tina-quant assay (Roche Diagnostics, Mannheim, Germany) on a Hitachi 917 analyzer (Roche Diagnostics). Tina-quant D-dimer is an immunoturbidimetric assay in which a beam of monochromatic light is passed through the suspension of latex microparticles coated by covalent bonding with monoclonal antibodies specific for D-dimer. The wavelength of the light is greater than the diameter of the latex microparticles and thus the solution of latex microparticles only slightly absorbs the light. In the presence of D-dimer, the particles aggregate and turbidity increases. The increase in scattered light is proportional to the amount of D-dimer in the test sample. The latex particles are coated with a monoclonal antibody that reacts with fibrin D-dimer or fragment D of fibrin. The antibody has no cross-reactivity with fibrinogen. This allows quantitative determination of D-dimer in human plasma. Normal limit of the assay is 500 µg/l. The test has a lower detectable limit of 40 µg/l [25,30–32].
The processing of data was computed using statistical package for social science (SPSS), version 14 IBM compatible PC (SPSS Inc., Chicago, Illinois, USA). Data were described in the form of number and percentage, and range and mean ± SD. In order to compare quantitative variables between two groups, both the Student's t-test and the nonparametric Mann–Whitney U-test were applied. A [chi]2-test was used to compare qualitative variables. A P-value of 0.05 or less and 0.01 or less was considered significant and highly significant, respectively, in all analyses.
Clinical, hematological and radiological features of gaucher patients
Type 1 Gaucher disease was found in 64.3% of patients, and type 3 in 35.7%. Molecular analysis of the acid GBA gene in 18 patients revealed homozygosity for L444P in 11 patients (all were type 3), whereas six type 1 Gaucher patients showed mutation of N370S and only one patient with type 1 Gaucher disease displayed the uncommon homozygous D409H mutation.
As shown in Table 1, age and sex did not differ significantly between patients in both groups, although positive family history for Gaucher disease was significantly present in type 3 compared with type 1 Gaucher patients (P < 0.05). Underweight was frequently observed in type 3 patients, whereas short stature was frequently observed in type 1 (P < 0.001). Mean hepatic and splenic volumes reported in multiples of normal size predicted for body weight in type 1 Gaucher disease were significantly higher when compared with those of type 3 patients (P < 0.001). White blood cell count, hemoglobin levels and platelet counts did not show any significant difference between both study groups of Gaucher disease (P > 0.05). Type 3 Gaucher patients received significantly higher doses of ERT compared with type 1 (P < 0.001).
As regards radiological findings (Table 1), in type 1 Gaucher disease, 21 patients (58%) had Erlenmeyer flask-shaped deformity in radiograph of long bones, as well as bone marrow expansion with cortical thinning in MRI. Moreover, 13 patients (36.1%) had ground glass appearance on HRCT chest. In type 3 Gaucher disease, nine patients (45%) had Erlenmeyer flask-shaped deformity in radiograph and bone marrow expansion with cortical thinning in MRI (Fig. 1). Fourteen patients (70%) had ground glass appearance in HRCT chest (eight of them had interlobular thickening). Pulmonary involvement shown by HRCT results (Figs 2 and 3) was present in a significantly higher percentage among type 3 Gaucher patients compared with type 1 (P < 0.05). Although bone changes represented by MRI findings were present in a higher percentage in type 1 compared with type 3 Gaucher disease, yet the difference did not reach statistical significance (P > 0.05). It was noticed that the studied Gaucher patients under ERT in a dosage of 60 U/kg per 2 weeks suffered from clinically and radiologically evident pulmonary symptoms confirmed by HRCT findings. However, when these patients received higher doses of ERT ranging from 90 to 120 U/kg per 2 weeks, a remarkable improvement in their clinical manifestations was observed. The frequency and severity of chest infections that required hospitalization were markedly decreased. There was decreased dyspnoea, clubbing and cyanosis in some patients, although on radiology, lung pathology was not normalized. Others showed improved respiratory compliance, with a significant improvement of the radiological findings.
D-dimer levels in control population and gaucher patients
D-dimer was negative (<500 µg/l) in controls with a range of 77.8–410 µg/l and a mean value of 215.7 ± 32.5 µg/l. All patients with Gaucher disease had significantly elevated D-dimer levels, with a range of 510–4329 µg/l and a mean of 2018 ± 368 µg/l at time of the study (P < 0.001). Patients with type 1 and type 3 Gaucher disease displayed significantly high D-dimer concentrations than controls when compared separately (P < 0.001) (Fig. 4). Moreover, D-dimer levels were significantly higher in type 3 patients compared with type 1 (mean, 1863.5 ± 414 vs. 830 ± 275.2 µg/l; P < 0.001) (Table 1 and Fig. 4).
D-dimer analysis results in relation to clinical and radiological data
Analysis of D-dimer in relation to clinical and radiological data of Gaucher patients (Table 2) revealed significantly higher levels in patients with abnormal MRI findings of long bones compared with those with normal MRI study (mean, 1563.6 ± 357 vs. 810.7 ± 250 µg/l; P < 0.001). In addition, Gaucher patients with pulmonary involvement on HRCT chest had higher D-dimer concentrations compared with those with normal radiological study (mean, 1980 ± 400 vs. 990 ± 205 µg/l; P < 0.001). Splenectomized patients displayed significantly higher D-dimer levels compared with nonsplenectomized patients (mean, 1670 ± 326 vs. 746 ± 187 µg/l; P < 0.001).
Table 2 Clinical and radiological features of the studied Gaucher patients according to D-dimer levels
Studies of genotype–phenotype correlations in Gaucher disease, the most common sphingolipidosis, revealed significant genotypic heterogeneity among clinically similar patients and vastly different phenotypes among patients with the same mutations . The incidence of the subacute neuronopathic (type 3) form is less than one in 100 000 patients. The distribution of type 3 Gaucher disease is panethnic, but this form predominates in some geographic regions such as northern Sweden [33,34]. In the present study, type 3 Gaucher disease was found in 35.7% of patients. This could be explained by the higher prevalence of the genotype L444P among this ethnic group as it was reported that N370S homozygotes generally present with a less severe phenotype, whereas L444P and D409H homozygosity confers neurologic involvement [2,4,35]. This is in contrast to Ashkenazi Jewish population in which the genotype N370S is predominant, resulting in higher prevalence of type 1 Gaucher disease with mild clinical manifestations . Moreover, some genetic mutations are unique to individual groups or families. For instance, D409H/D409H causes calcification of the heart valves and occulomotor apraxia, but without visceral affection occurring uniquely in Jenin Arabs, Japanese and Spanish patients [36,37].
Failure to thrive and underweight were prominent features in the studied patients, especially in type 3 Gaucher disease. In line with our results, Zimran et al.  noticed that poor weight gain and growth retardation in those patients occurred likely due to the excessive metabolic burden from accumulation of undegraded substrate and GLC in tissues, together with the chronic nature of the disease and anemia that accounts for the chronic fatigue reported by many patients. The low-grade, smoldering and subclinical internal inflammation in individuals with Gaucher disease is accompanied by an increased degree of erythrocyte and leukocyte adhesiveness/aggregation. These findings might have rheological consequences in terms of microcirculatory slow flow and tissue hypoxemia. An additional factor in type 3 Gaucher patients is pseudobulbar palsy resulting in dysphagia, regurgitation and recurrent aspiration pneumonia . Similarly, Khalifa et al.  reported that patients with Gaucher disease were more susceptible to recurrent infection, which is a main cause of debilitation. The tendency toward infection in Gaucher disease patients was attributed to their postsplenectomy state. Furthermore, Orvisky et al.  noticed resumption of normal growth in children after receiving ERT.
As previously reported, the estimated life expectancy for patients with type 1 Gaucher disease was mildly decreased than the reference population being 9 years less . Disease progression varies in type 1 Gaucher disease and survival may be normal depending on the severity of complications. On the contrary, evolution is rapid in type 2 Gaucher disease leading to death within the first 2 years of life, usually because of lung failure, whereas type 3 Gaucher disease patients often survive to the second or third decades of life [2,42]. In this study, the significantly higher doses of ERT received by patients with type 3 Gaucher disease compared with type 1 were in concordance to the report of Vellodi et al. , who stated that there is clear evidence that ERT improves systemic involvement in nonneuronopathic as well as neuronopathic Gaucher disease enhancing quality of life. In addition, ERT has reversed, stabilized or slowed the progression of neurological involvement in some patients and is considered the gold standard treatment for Gaucher disease type 1 and type 3 patients [27,43,44]. High dose provides a faster clinical response and should be considered for patients with more aggressive disease .
Despite some general genotype–phenotype correlations, disease severity and clinical outcomes cannot be predicted on the basis of genotype [13,46]. Genetic modifiers may play an important role in determining the eventual Gaucher phenotype . Identification of biochemical markers characteristic of pathology may be of use in predicting the progression of the disease state [23,34,47]. There are no predictive tests to ascertain patients at risk for bone and lung involvement in Gaucher disease, which are slow to respond to ERT [4,9]. As reported by Deghady et al. , bleeding tendency in Gaucher disease may not always be related to absolute platelet counts, but may be influenced by coagulation factor deficiencies or abnormal platelet function. Acquired coagulation factor deficiencies have been demonstrated in Gaucher disease. The mechanism involved is unclear, but may include low-grade disseminated intravascular coagulation or sequestration of coagulation factors by substrate-loaded cells .
Quantitative D-dimer determination has become routine practice in patients evaluated for the presence of deep venous thrombosis or pulmonary emboli [25,49]. In this study, plasma fibrin D-dimer was assayed in Gaucher disease using a new quantitative latex test for cross-linked fibrin degradation products, involving a specific monoclonal antibody. This method has been proven to be rapid, sensitive and reproducible .
The relevance of the determination of D-dimer in Gaucher disease was evaluated and high plasma D-dimer levels were found among patients with Gaucher disease, especially type 3. In addition, a significant elevation was observed in those with bone changes and pulmonary involvement as reflected by radiological findings. In agreement with our results, Shitrit et al.  stated that the levels of elevated of D-dimers were related to the presence of pulmonary infiltration, by Gaucher cells, as well as bone marrow infiltration. They implied that microthrombi may be part of the pathogenesis for avascular necrosis as well as pulmonary hypertension in patients with Gaucher disease. The significant correlation of D-dimer levels with treatment may be an indirect marker of bone and/or lung in Gaucher disease . Additionally, Boot et al.  and Maire et al.  reported that the elevation of the serum concentration of several serologic markers (e.g. D-dimer, CCL18/PARC, CD163) in persons with Gaucher disease is considered a possible surrogate indicator of disease burden that could be used in monitoring treatment response.
Moreover, it was reported that a normal MRI study in Gaucher patients with elevated D-dimer levels does not rule out subsequent development of bony changes in those patients, especially if splenectomized. Therefore, serial follow-up is required and the rising titer of D-dimer may determine or indicate the proper timing of the next MRI study .
Strikingly, higher D-dimer concentrations were found among splenectomized patients with Gaucher disease. These results were in line with those obtained by Ashkenazi et al. , who observed that patients with Gaucher disease usually start to suffer from severe bony manifestations and pulmonary hypertension after splenectomy. In a preliminary study, Tunaci et al.  reported that asplenia was strongly associated with life-threatening forms of pulmonary hypertension in Gaucher disease, as removal of the spleen, which is the primary reservoir of storage cells, promotes migration of the mononuclear phagocyte system toward other tissue macrophage pools (lung and bone). Recently, Mistry et al.  observed a higher risk of avascular necrosis was observed among patients who had previously undergone splenectomy.
Bone involvement was evident clinically and radiologically in the studied patients with type 1 Gaucher disease while pulmonary involvement reflected by HRCT findings was significantly found among type 3 Gaucher disease compared to type 1. This finding could be explained by the significantly elevated D-dimer levels encountered in type 3 Gaucher patients compared to type 1 Gaucher disease which is a less severe form. In this context, El-Beshlawy et al.  reported that bone manifestations were the most common presenting symptoms in Egyptian patients with type 1 Gaucher disease as evidenced by MRI long bones and ERT was effective in ameliorating radiological manifestations of skeletal disease and achieving complete remission of bone pain but it required a long period of treatment. Moreover, Jmoudiak and Futerman  reported that lung involvement including interstitial lung disease and pulmonary hypertension was found in a small number of patients with type 1 Gaucher disease. Additionally, Miller et al.  reported a higher frequency of pulmonary involvement in type 3 Gaucher disease compared to type 1. On the other hand, few patients develop pulmonary hypertension on ERT . Mistry et al.  also revealed a remarkable predisposition for pulmonary hypertension in type 1 Gaucher disease. Progression to severe, life-threatening pulmonary hypertension occurs in the presence of additional genetic factors (non-N370S GBA mutation, positive family history and angiotensin converting enzyme I gene polymorphism) and epigenetic modifiers (i.e. asplenia, female sex) . Therefore, routine echocardiographic monitoring of all treated and untreated patients with type 1 Gaucher disease was recommended and consideration of treatment withdrawal was suggested if the TI gradient progresses to more than 30 mmHg .
In the present analysis, the remarkable improvement occurred in pulmonary manifestations with higher doses of ERT confirmed the previous reports by Elstein et al.  and Ashkenazi et al. , who noticed that the lung and bone are less accessible compartments to ERT, so that a low-dose regimen may not be sufficient to overcome a threshold for Gaucher cell infiltration and the dose must be increased to allow an adequate enzyme concentration at the site of the pathology, especially if there are fibrotic or necrotic regions. Moreover, Goitein et al.  reported that in patients with Gaucher disease and symptomatic lung involvement, there is great heterogeneity in presentation and response to ERT. Clinically, some benefited significantly from ERT, but in contrast to the dramatic reduction in organomegaly, there was no normalization in pulmonary function or lung architecture. These findings emphasized the importance of optimal dose of ERT, avoidance of splenectomy and vigorous combination therapy with vasodilators, as appropriate for the best outcomes in Gaucher patients [16,29,43].
In conclusion, elevated D-dimer levels in Gaucher patients can be used as a predictor for the development of skeletal and pulmonary complications and may suggest that the occurrence of these pathological changes is induced initially as microthrombi. Thereafter, it would be interesting to apply the fully quantitative automated D-dimer assay in a prospective manner to ‘borderline’ Gaucher patients with persistent dyspnea, bronchorrhea and recurrent pneumonopathy, to ascertain whether they have merely incipient pulmonary changes and follow-up them for the possibility of developing progressive pulmonary hypertension. Further studies are recommended to indicate whether a predictive cut-off level of D-dimer in Gaucher disease can be described.
[1.] Meikle PJ, Hopwood JJ. Lysosomal storage disorders: emerging therapeutic options require early diagnosis. Eur J Pediatr 2003; 162(Suppl. 1):S34–S37.
[2.] Martins AM, Valadares ER, Porta G, Coelho J, Filho JS, Pianovski MAD, et al. Recommendations on the diagnosis, treatment, and monitoring of Gaucher disease. J Pediatr 2009; 155(Suppl. 2):S10–S18.
[3.] Mehta A. Epidemiology and natural history of Gaucher's disease. Eur J Intern Med 2006; 17:S2–S5.
[4.] Beutler E, Grabowski GA. Gaucher disease. In: Scriver CR, Valle D, Beudet A, Sly WS, editors. The metabolic and molecular bases of inherited diseases. Volume III. New York: McGraw-Hill; 2001. pp. 3635–3668.
[5.] Urban DJ, Zheng W, Goker-Alpan O, Jadhav A, Lamarca ME, Inglese J, et al. Optimization and validation of two miniaturized glucocerebrosidase enzyme assays for high throughput screening. Comb Chem High Throughput Screen 2008; 11:817–824.
[6.] Grabowski GA. Gaucher disease: lessons from a decade of therapy. J Pediatr 2004; 144:S15–S19.
[7.] Mignot C, Doummar D, Maire I, de Villemeur TB. Type 2 Gaucher disease: 15 new cases and review of the literature. Brain Dev 2006; 28:39–48.
[8.] Orvisky E, Park JK, LaMarca ME, Ginns EI, Martin BM, Tayebi N, et al. Glucosylsphingosine accumulation in tissues from patients with Gaucher disease: correlation with phenotype and genotype. Mol Genet Metab 2002; 76:262–270.
[9.] Shitrit D, Rudensky B, Zimran A, Elstein D. D-Dimer assay in Gaucher disease: correlation with severity of bone and lung involvement. Am J Hematol 2003; 73:236–239.
[10.] Hughes D, Cappellini MD, Berger M, Droogenbroeck JV, de Fost M, Janic D, et al. Recommendations for the management of the haematological and onco-haematological aspects of Gaucher disease. Br J Haematol 2007; 138:676–686.
[11.] Sidransky E. Gaucher disease: complexity in a ‘simple’ disorder. Mol Genet Metab 2004; 83:6–15.
[12.] Mistry P, Germain DP. Phenotype variations in Gaucher disease. Rev Med Interne 2006; 27(Suppl. 1):S3–S10.
[13.] Jmoudiak M, Futerman AH. Gaucher disease: pathological mechanisms and modern management. Br J Haematol 2005; 129:178–188.
[14.] Poll LW, Maas M, Terk MR, Roca-Espiau M, Bembi B, Ciana G, et al. Response of Gaucher bone disease to enzyme replacement therapy. Br J Radiol 2002; 75(Suppl. 1):A25–A36.
[15.] Elstein D, Hadas-Halpren I, Azuri Y, Abrahamov A, Bar-Ziv Y, Zimran A. Accuracy of ultrasonography in assessing spleen and liver size in patients with Gaucher disease: comparison to computed tomographic measurements. J Ultrasound Med 1997; 16:209–211.
[16.] Vom Dahl S, Poll L, Di Rocco M, Ciana G, Denes C, Mariani G, et al. Evidence-based recommendations for monitoring bone disease and the response to enzyme replacement therapy in Gaucher patients. Curr Med Res Opin 2006; 22:1045–1064.
[17.] Wenstrup RJ, Roca-Espiau M, Weinreb NJ, Bembi B. Skeletal aspects of Gaucher disease: a review. Br J Radiol 2002; 75:A2–A12.
[18.] Maas M, Hangartner T, Mariani G, McHugh K, Moore S, Grabowski GA, et al. Recommendations for the assessment and monitoring of skeletal manifestations in children with Gaucher disease. Skeletal Radiol 2008; 37:185–188.
[19.] Lee S, Mark A, Huen K, Lam S, Chow C. Gaucher disease with pulmonary involvement in a 6 years old girl: report of resolution of radiographic abnormalities. J Pediatr 2001; 139:862–864.
[20.] McHugh K, Olsen E ØE, Vellodi A. Gaucher disease in children: radiology of noncentral nervous system manifestations. Clin Radiol 2004; 59:117–123.
[21.] Grabowski G, Leslie N, Wenstrup R. Enzyme therapy for Gaucher disease: the first 5 years. Blood Rev 2003; 9:115–133.
[22.] Mistry PK, Sirrs S, Chan A, Pritzker MR, Duffy TP, Grace ME, et al. Pulmonary hypertension in type 1 Gaucher's disease: genetic and epigenetic determinants of phenotype and response to therapy. Mol Genet Metab 2002; 77:91–98.
[23.] Boot RG, van Reemen MJ, Wegdam W, Sprenger RR, de Jong S, Speijer D, et al. Gaucher disease: a model disorder for biomarker discovery. Expert Rev Proteomics 2009; 6:411–419.
[24.] Wells P, Anderson D, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 2003; 349:1227–1235.
[25.] Korte W, Riesen W. Latex-enhanced immunoturbidimetry allows D-dimer determination in plasma and serum samples. Clin Chem 2000; 46:871–872.
[26.] Hollak CE, van Weely S, van Oers MH, Aerts JM. Marked elevation of plasma chitotriosidase activity: a novel hallmark of Gaucher disease. J Clin Invest 1994; 93:1288–1292.
[27.] de Fost M, Hollak CE, Groener JE, Aerts JM, Maas M, Poll LW, et al. 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 2006; 108:830–835.
[28.] Pastores GM. Recombinant glucocerebrosidase (imiglucerase) as a therapy for Gaucher disease. BioDrugs 2010; 24:41–47.
[29.] Hollak CE, de Fost M, van Dussen L, Vom Dahl S, Aerts JM. Enzyme therapy for the treatment of type 1 Gaucher disease: clinical outcomes and dose-response relationships. Expert Opin Pharmacother 2009; 10:2641–2652.
[30.] Schutgens REG, Haas FJLM, Ruven HJT, Spannagl M, Horn K, Biesma DH. No influence of heparin plasma and other (pre)analytic variables on D-dimer determinations. Clin Chem 2002; 48:1611–1613.
[31.] Weber T, Högler S, Auer J, Berent R, Lassnig E, Kvas E, et al. D-Dimer in acute aortic dissection. Chest 2003; 123:1375–1378.
[32.] Wieganda J, Kollerb M, Bingissera R. Does a negative D-dimer test rule out aortic dissection? Swiss Med Wkly 2007; 137:462.
[33.] Boot RG, Verhoek M, de Fost M, Hollak CE, Maas M, Bleijlevens B, et al. Marked elevation of the chemokine CCL18/PARC in Gaucher disease: a novel surrogate marker for assessing therapeutic intervention. Blood 2004; 103:33–39.
[34.] Maire I, Guffon N, Froissart R. Current development and usefulness of biomarkers for Gaucher disease follow up. Rev Med Intern 2007; 28(Suppl. 2):S187–S192.
[35.] Barranger J, Rice E. An overview of Gaucher disease. Gaucher Clin Perspect 1993; 1:1–5.
[36.] Tayebi N, Park J, Madike V, Sidransky E. Gene rearrangement on 1q21 introducing a duplication of the glucocerebrosidase pseudogene and a metaxin fusion gene. Hum Genet 2000; 107:400–403.
[37.] Beutler E. Gaucher disease: multiple lessons from a single gene disorder. Acta Paediatr Suppl 2006; 95:103–109.
[38.] Zimran A, Bashkin A, Elstein D, Rudensky B, Rotstein R, Rozenblat M, et al. Rheological determinants in patients with Gaucher disease and internal inflammation. Am J Hematol 2004; 75:190–194.
[39.] Mistry P. Phenotype variations in Gaucher disease. Rev Med Intern 2006; 27:S3–S6.
[40.] Khalifa A, Tantawy A, Monir E, Sadek A, Tiseer N. Immune dysfunction in patients with Gaucher disease: impact of disease severity and enzyme replacement therapy. Haematologica 2010; 95(suppl.2):37.
[41.] Weinreb NJ, Deegan P, Kacena KA, Mistry P, Pastores GM, Velentgas P, et al. Life expectancy in Gaucher disease type 1. Am J Hematol 2008; 83:896–900.
[42.] Grabowski GA. Phenotype, diagnosis, and treatment of Gaucher's disease. Lancet 2008; 372:1263–1271.
[43.] Vellodi A, Bebi B, de Villemeur TB, Collin-Histed T, Erikson A, Mengel E, et al. Management of neuronopathic Gaucher disease: a European consensus. J Inherit Metab Dis 2001; 24:319–327.
[44.] Cox TM, Aerts JM, Andria G, Beck M, Belmatoug N, Bembi B, et al, Advisory Council to the European Working Group on Gaucher disease. The role of the iminosugar N butyldeoxynojirimycin (miglustat) in the management of type I (nonneuronopathic) Gaucher disease: a position statement. J Inherit Metab Dis 2003; 26:513–526.
[45.] Altarescu G, Schiffmann R, Parker CC, Moore DF, Kreps C, Brady RO, Barton NW. Comparative efficacy of dose regimens in enzyme replacement therapy of type I Gaucher disease. Blood Cells Mol Dis 2000; 26:285–290.
[46.] El-Beshlawy A, Ragab L, Youssry I, Yakout K, El-Kiki H, Eid K, et al. Enzyme replacement therapy and bony changes in Egyptian pediatric Gaucher disease patients. J Inherit Metab Dis 2006; 29:92–98.
[47.] Whitfield PD, Nelson P, Sharp PC, Bindloss CA, Dean C, Ravenscroft EM, et al. Correlation among genotype, phenotype, and biochemical markers in Gaucher disease: implications for the prediction of disease severity. Mol Genet Metab 2002; 75:46–55.
[48.] Deghady A, Marzouk I, El-Shayeb A, Wali Y. Coagulation abnormalities in type 1 Gaucher disease in children. Pediatr Hematol Oncol 2006; 23:411–417.
[49.] Schutgens R, Haas F, Gerritsen W, Van-der Horst F, Nieuwenhuis H, Biesma D. The usefulness of five D-dimer assays in the exclusion of deep venous thrombosis. J Thromb Haemost 2003; 1:976–981.
[50.] Ashkenazi A, Zaizov R, Matoth Y. Effect of splenectomy on destructive bone changes in children with chronic (type I) Gaucher disease. Eur J Pediatr 2003; 145:138–141.
[51.] Tunaci A, Berkmen YM, Gokmen E. Pulmonary Gaucher's disease: high-resolution computed tomographic features. Pediatr Radiol 1995; 25:237–238.
[52.] Mistry PK, Deegan P, Vellodi A, Cole JA, Yeh M, Weinreb NJ. Timing of initiation of enzyme replacement therapy after diagnosis of type 1 Gaucher disease: effect on incidence of avascular necrosis. Br J Haematol 2009; 147:561–570.
[53.] Miller A, Brown LK, Pastores GM, Desnick RJ. Pulmonary involvement in type I Gaucher disease: functional and exercise findings in patients with and without clinical interstitial lung disease. Clin Genet 2003; 63:368–376.
[54.] Elstein D, Klutstein M, Lahad A, Abrahamov A, Hadas-Halpern I, Zimran A. Echocardiographic assessment of pulmonary hypertension in Gaucher disease. Lancet 1998; 351:1544–1546.
[55.] Goitein O, Elstein D, Abrahamov A, Hadas-Halpern I, Melzer E, Kerem E, et al. Lung involvement and enzyme replacement therapy in Gaucher's disease. QJM 2001; 94:407–415.