Epidemiology

GD type 1 (GD-1) is the most frequent lysosomal storage disorder and a pan-ethic disorder (prevalence estimated for the world population 1: 40 000–60 000), whereas the frequency in the Askanazi Jewish population is much higher (1: 400–1000). In the United Kingdom about 1000–1500 GD-1 patients have been estimated . However, calculations for the prevalence of GD are difficult and vary between studies from different countries. This may be due to the fact that many patients with GD-1 may face only very few or atypical clinical symptoms, thus diagnosis of all affected persons is hard or even impossible, also in view of different diagnostic possibilities of countries around the world.

Types of GD

The symptoms associated with GD are due to the progressive accumulation of Gaucher cells in various organs. Thus, GD is a multisystemic disorder with disease manifestation at all ages dependent on the subtype of GD. Three basic clinical forms of GD can be distinguished depending on the degree of neurological involvement; however, today the different forms of GD are considered rather to reflect a continuum ranging from early onset to late onset disease and from severe forms with neurological symptoms to mild forms with solely visceral manifestations . GD-1 is the most frequent form and accounts for 94% of all registered GD cases according to the Gaucher Registry . It leads to a chronic course of disease and the organs frequently affected are the spleen, liver, bone marrow and bone and, in severe cases, also the lung and kidney. Hepatosplenomegaly and haematological complications including anaemia and thrombocytopenia with bleeding are common in untreated GD-1 . Acute neuronopathic GD (GD-2) manifests in early childhood, neurological deterioration progresses quickly and death generally occurs within the age of 2 years. Subacute neuronopathic GD (GD-3) shows a slower neurological involvement and usually occurs in adolescence .

Types of GD

The symptoms associated with GD are due to the progressive accumulation of Gaucher cells in various organs. Thus, GD is a multisystemic disorder with disease manifestation at all ages dependent on the subtype of GD. Three basic clinical forms of GD can be distinguished depending on the degree of neurological involvement; however, today the different forms of GD are considered rather to reflect a continuum ranging from early onset to late onset disease and from severe forms with neurological symptoms to mild forms with solely visceral manifestations . GD-1 is the most frequent form and accounts for 94% of all registered GD cases according to the Gaucher Registry . It leads to a chronic course of disease and the organs frequently affected are the spleen, liver, bone marrow and bone and, in severe cases, also the lung and kidney. Hepatosplenomegaly and haematological complications including anaemia and thrombocytopenia with bleeding are common in untreated GD-1 . Acute neuronopathic GD (GD-2) manifests in early childhood, neurological deterioration progresses quickly and death generally occurs within the age of 2 years. Subacute neuronopathic GD (GD-3) shows a slower neurological involvement and usually occurs in adolescence .

Pathogenesis of Gaucher disease

Glucocerebroside is insufficiently broken down into ceramide and glucose due to GBA deficiency leading to a progressive accumulation of glucocerebroside in the lysosomes of macrophages in various organs . In addition, interactions with lipid metabolism (lipid phospatidylserine, saposin C), calcium homeostasis or enzyme misfolding of GBA inducing endoplasmatic reticulum stress may additionally contribute to the pathologies of GD. The current understanding of pathophysiological determinants in GD has been summarised recently .

Concerning the clinical symptoms of GD-1, the organomegaly of the liver and spleen can be well explained by the progressive storage of glucocerebroside. Also the haematological pathologies (anaemia and thrombocytopenia) find an explanation by the progressive displacement of the red bone marrow by Gaucher cells. However, the pathogenesis of bone changes in GD-1 has not yet been fully resolved and seems to be of complex origin .

The pathological cascade starts with the progressive accumulation of glucocerebrosides within the bone marrow cavity leading to a centrifugal expansion of the red bone marrow. The spine, pelvis and the diaphysial region of the femur and humerus are initially involved. The displacement of inactive yellow marrow by red marrow in the periphery alters vascularity and local pressures possibly leading to thrombosis or infarction by Gaucher cells. Pathologies such as bone crises, avascular necrosis, bone infarcts and localised cortical thinning may be explained in part by these effects. In addition, accumulation of glucocerebrosides seems to induce macrophage activation which may promote additional inflammatory processes due to the altered expression of different macrophage-derived factors and cytokines .( Table 1 ).

The activity of osteoclasts and osteoblasts are influenced by a variety of hormones including oestrogen, testosterone, parathyroid hormone or thyroid hormone. The effects of hormones on the skeleton can be mediated either directly by hormone receptors located on osteoblasts and osteoclasts or indirectly by various other cells of the immune system. Changes of cytokines including inflammatory mediators, such as interleukin (IL)-1, IL-6, tumour necrosis factor-alpha (TNF-α), consequently influence osteoclast and osteoblast activity. An overview of altered cytokine release in GD is given in Table 1 . In particular, the changes of some cytokines that seem to be of relevance to the development of osteoporosis in GD: IL-10 activity may inhibit the osteoblasts activity , whereas IL-1β, IL-6 and M-CSF could enhance bone resorption due to increased osteoclast activation and formation . Furthermore, macrophage inflammatory protein (MIP)-1α and MIP-1β, which have been shown to increase the bone resorption by osteoclasts in multiple myeloma , were also elevated in GD-patients with bone disease , thus also possibly contributing with other cytokines to pathological bone resorption in GD. Changes in total T-lymphocyte numbers and alterations of CD4+/CD8 + T-lymphocyte ratios may be a further factor, as an overall decrease of T-lymphocytes with lower CD8 + T-lymphocyte numbers has been reported in GD-patients with bone involvement .

This cross-talk of immune cell-osteoclast/osteoblast interactions, known as ‘osteoimmunology’, reveals bone metabolism to be a complex network of interacting factors including bone marrow and immune and bone cells . In GD, the complex interactions of cells of the bone marrow with bone, and as two separate compartments closely interacting with each other, may explain some of the changes seen in bone disease with GD. However, the development of the different bone pathologies in GD still requires a full explanation, but a complex, multifactorial pathogenesis as pointed out is likely .

Metabolic changes of bone disease in GD

Different markers of bone turnover have been evaluated in treatment-naïve patients and on enzyme replacement therapy (ERT) , recently also in patients switching from ERT to substrate reduction therapy (SRT) . Until recently the pathogenesis of bone loss in GD was based on the thesis of increased bone resorption. However, when looking at markers of bone turnover, this concept solely based on increased osteoclast activity in GD has to be questioned . Those studies evaluating treatment-naïve patients revealed normal or decreased markers of bone formation, whereas markers of bone degradation were mainly normal or increased . Only Drugan et al. reported decreased levels of carboxyterminal telopeptide of type I collagen (CTx) and even more decreased levels of osteocalcin (OC), indicating a dysbalance in bone remodelling. Studies investigating GD-patients on ERT revealed markers of unchanged or increased bone formation and unchanged or decreased bone degradation. In the study by Sims et al. , the changes on ERT versus baseline values were also quantified: during ERT, bone formation increased by 60% and bone resorption decreased by 20–40%.

Small patient groups and the use of less-sensitive bone markers in some studies may explain why not all studies could demonstrate consistent results concerning bone metabolism in GD . However, when looking at the newer markers of bone turnover, it seems that GD-patients may face both increased bone degradation and impaired bone formation leading to osteoporosis . Thus, the current concept on the pathogenesis of osteoporosis development in GD seems to need revision involving additional impaired osteoblast activity. In a recent study, van Dussen et al. proposed, in contrast to earlier hypotheses, that the decrease in bone mineral density (BMD) in GD-patients is primarily based on a decrease in bone formation. In their series, OC was decreased indicative of a decreased bone formation, whereas the bone resorption markers CTx and N-terminal propeptide of type 1 procollagen were within the normal range for most patients . In addition, OC concentration was negatively correlated to measures of overall disease severity and positively correlated with imaging data, suggesting a relation with disease severity . The predominance of disturbed osteoblastic function in GD was also supported by results of a recent study in GBA gene-deficient mice .

Cathepsin K : C athepsin K (CatK) mediates bone matrix destruction. CatK was two- to threefold increased in sera from GD-patients as compared to healthy controls . After treatment with ERT serum, CatK activities decreased significantly. Increased CatK levels may thus be involved in the development of osteoporosis or lytic bone lesions .

Osteoprotegerin : The activity of osteoclasts and osteoblasts is regulated by the OPG (osteoprotegerin)/RANK (Receptor Activator of NF-kB)/RANKL (Receptor Activator of NF-kB Ligand) system, which plays a central role in bone metabolism. Interestingly, osteoprotegerin (OPG) levels in GD-patients were comparable to controls . Thus, changes of bone metabolism seem not to be mediated via the OPG/RANKL system .

Vitamin D : Data on vitamin D in GD-patients is limited . Parisi et al. found in nine young GD-patients a vitamin D deficiency with 25-OH vitamin D levels <30 ng ml ⁻¹ (<75 nmol l ⁻¹ ) in all patients. Mikosch et al. ³² observed in 60 GD-1 patients varying degrees of vitamin D deficiency in the majority of these patients. Using a cut-off value of 32 ng ml ⁻¹ (80 nmol l ⁻¹ ), 73.7% showed vitamin D deficiency during June–November and 92.9% during the period December–May. BMD was positively correlated to the vitamin D values measured during December–May, representing the seasonal nadir of vitamin D .

Gaucher disease and bone involvement

In GD, pathologies of the bone and bone marrow have been underestimated. Now, according to literature, bone involvement is described to occur in approximately 75% of GD-1 patients . With the systematic use of various imaging modalities, the frequency of any bone involvement in GD-1 has been reported to be even more than 90% .

The skeletal manifestations of GD include a variety of bone pathologies. The progressive storage of glucocerebroside in the bone marrow is associated with osteopenia and osteoporosis which may lead to fractures. Avascular bone necrosis, most frequently within the hip joints, cortical thinning, lytic bone lesions, osteosclerosis and, rarely, acute osteomyelitis are further skeletal complications of GD-1 . Furthermore, extraosseous manifestation of bone can be seen as a rare complication in severe disease. In the long term, the most severe and disabling complications in GD-1 are associated with the involvement of the skeleton . Early manifestation of GD during childhood leads to growth retardation and a pathological growth pattern with tubulation of the metaphysic of the area of the long bone, in particular, the distal metaphysic of the femur and proximal metaphysic of the tibia.

Bone involvement is also present to a varying extent in GD-3, whereas children with GD-2 show no clinically relevant bone involvement since rapid neurological deterioration leads to death till the age of 2 years, prior to the onset of bone pathology.

In most patients, bone disease in GD shows a progressive course over years . Overall, the bone manifestations in GD are one of the most debilitating aspects of the disease . From a clinical point of view, GD-patients frequently face acute or chronic episodes of dull, achy bone pain of varying intensity. The clinical symptoms of bone disease in GD and its complications like bone crisis, avascular necrosis with joint destructions or fractures place a heavy burden on the patients’quality of life .

In a review on the skeletal aspects of GD, Wenstrup et al. . divided the bone pathologies associated with GD into three groups including (a) focal disease (irreversible lesions – e.g., osteonecrosis and osteosclerosis), (b) local disease (reversible abnormalities adjacent to heavily involved marrow – e.g., cortical thinning and bone deformities) and (c) generalised osteopenia. However, this descriptive and morphologically orientated division of bone pathologies in GD does not explain the different pathologies. Apart from this division, GD might also be seen as a sequence of events ( Fig. 1 ). Bone pathologies seen in GD may be divided up into primary, secondary and tertiary changes . Primary changes are likely to be due to altered cytokine expression or increased local pressure. Upon ERT, these pathologies are at least partly reversible. Secondary changes, such as bone infarcts, may evolve out of complex pathological mechanisms including changes of cytokine release, alteration of vascularity and increased local pressure due to extensive glucocerebroside accumulation. Clinically, these pathologies are acute events often accompanied by severe bone pain. Tertiary changes summarise those rather chronic pathologies seen as further deterioration evolving out of secondary, firstly acute, changes. Secondary and tertiary changes will leave scars within the bone and bone marrow which will remain unchanged even on ERT ( Fig. 1 ).

Overview of bone pathologies in GD seen as a sequence of events dividing them into primary, secondary and tertiary bone changes. Reprinted with permission from .

Growth retardation during childhood : Growth retardation has been reported in GD . After initiation of ERT, most patients showed growth acceleration and regained normal weight .

Erlenmeyer flask deformity : The Erlenmeyer flask deformity (EFD) describes a distinct abnormality of the distal femora, occasionally also within the metaphyseal region of other tubular bones, in particular, the proximal tibia. EFD results from impaired modelling within the di-metaphysis and abnormal cortical thinning, due to local bone marrow infiltration by Gaucher cells . This leads to a lack of the typical concave di-metaphyseal curve resulting in an Erlenmeyer flask-like appearance . EFD, although common in GD, is not pathognomonic for GD. Recently, Faden et al. described 20 distinct disorders associated with EFD.

Osteopenia, Osteoporosis : Reduced bone density is common in GD and is associated with an increased risk of fracture. Generalised osteopenia correlates with overall disease severity; vertebral density was an independent predictor of the severity of bone involvement .

Osteolytic lesions : Focal osteolytic lesions are frequently seen in GD, which may be combined with other localised pathologies such as cortical thinning or bone extensions.

Bone infarcts, osteonecrosis, osteomyelitis and osteosclerosis : Bone infarcts ( Fig. 2 ) can occur without clinical symptoms or only slight pain, but can also present with sudden onset of localised pain, tenderness, erythema and swelling. Such episodes of severe bone pain, also called ‘bone crisis’, are frequently accompanied by fever, elevated leucocytes and an accelerated erythrocyte sedimentation rate. In GD, acute focal bone involvement usually causes aseptic osteomyelitis, whereas ‘true osteomyelitis’ is rare. However, clinical differentiation between aseptic and pyogenic osteomyelitis is difficult or even impossible at the time of onset but, in time, negative blood cultures or aspirates can exclude pyogenic osteomyelitis. Osteonecrosis ( Fig. 3 ) is believed to be secondary to ischaemia due to chronic infarction. It is an irreversible process and it predominantly affects the femoral head, proximal humerus and vertebral bodies, resulting in possible fractures and joint collapse ( Figs. 3 and 4 ). After bone infarction, focal osteosclerosis or osteoarthritis may develop.

MRI femora, T1 and STIR images: several bone infarcts within the diaphysial region of both femura and the right tibia. Normal appearance of the left tibia. Erlenmeyer flask deformity, right femur.

MRI femora, T1 and STIR images: patchy hypointensive signals due to bone marrow infiltration of the pelvis and the left hip in the T1 images. Right hip with avascular necrosis and joint deformation (arrow).

MRI lumbar and thoracic spine, T1 and STIR images: bone marrow infiltration by Gaucher cells showing diffuse hypointensive signals in the T1 and STIR images. In addition, a vertebral fracture is present of L5 (arrow).

Cortical thinning and long bone deformity : Cortical thinning and long bone deformity are frequently seen in areas adjacent to bone marrow infiltration.

Extraosseous manifestation : A very rare skeletal manifestation in GD is an extraosseous extension of Gaucher cells, which occurs after cortical destruction and extraosseous extension into tissue adjacent to the bone. It has to be regarded as a manifestation of severe bone disease and, so far, only few cases have been described . The differential diagnoses for extraosseous extension include osteomyelitis and haematological malignancy. Magnetic resonance imaging (MRI) and the biopsy of the lesion or, if clinically necessary, its surgical removal, will lead to the diagnosis.

Symptoms and impact on quality of life

GD-patients usually experience localised or diffuse bone pain of varying intensity, whereas during bone crisis or in the course of fractures they exhibit severe pain. Bone infarcts and avascular necrosis (most frequently of the hip) can lead to progressive functional impairment or even destruction of joints necessitating joint replacement . Furthermore, the development of osteoporosis increases the risk of fractures. Overall, the different bone manifestations in GD have a high impact on the mobility of GD-patients. In the long term, for patients with GD-1, the skeletal involvement is probably the most striking and disabling feature, leading to significant pain and progressive loss of quality of life . Up to 20% of GD-patients have impaired mobility .

Diagnostic approaches to bone manifestations in GD

The extent of bone involvement in GD cannot be estimated by sole clinical examination, thus necessitating bone imaging. Different imaging modalities are available to evaluate bone manifestation in GD (disease burden, presence of skeletal complications and follow-up after treatment).

X-ray : Plain radiography shows a low sensitivity in detecting skeletal pathologies in GD . However, it can be used in the detection of bone complications such as fractures or dislocation of joint replacements. It is regarded as the method of choice for the evaluation of joint arthroplasty . X-ray can detect local deformities of bone including Erlmeyer flask deformity, cystic or tumorous lesions and localised cortical thinning .

MRI : MRI visualises with high sensitivity all morphological bone manifestations seen in GD ( Fig. 2–4 ). T1-weighted and T2-weighted spin echo sequences, short tau inversion recovery (STIR) sequences and turbo spin echo (TSE) are the most frequently used MRI modalities . MRI spin echo sequences can sensitively image the fat content of bone marrow in adults . Normal yellow marrow creates a hyperintensive T1-weighted and an intermediate to hyperintensive T2-weighted signal. The infiltration of bone marrow by Gaucher cells creates hypointensive signals ( Fig. 4 ). Patients on ERT show a normalisation of signal intensity due to the reduction of Gaucher cell deposition and increase in fatty yellow marrow. MRI is the method of choice to evaluate the extent of bone disease prior to therapy and during follow-up in patients on therapy . It is also the most sensitive method to detect femoral head necrosis ( Fig. 3 ).

Quantitative chemical shift imaging (QCSI) : QCSI is a quantitative MRI technique which measures fat content in the axial bone marrow and the extent of its displacement by Gaucher cells . The quantification is based on differences of resonant frequencies of water and triglycerides . The normal triglyceride-rich bone marrow is displaced by Gaucher cells leading to an altered fat content of the region. QCSI has to be regarded the gold standard to quantify bone marrow involvement in GD ; however, QCSI is available only in few centres.

Semi-quantitative scoring systems of bone disease : Several scoring systems (Düsseldorf Gaucher Score, bone marrow burden, vertebral disc ratio (VDR), Spanish-MRI score (S-MRI), Terk Classification and Rosenthal Score) have been established to quantify the severity and extent of bone involvement . Scoring systems, such as bone marrow burden or S-MRI , can be regarded as a good alternative to QCSI in daily routine . Studies have shown an improvement of bone marrow involvement on ERT and SRT using either the bone marrow burden or the S-MRI scoring system. Scoring systems are regarded to be beneficial in evaluating the extent of bone involvement of GD-patients prior to therapy and during follow-up.

Scintigraphy : Although scintigraphic methods are not first-line methods for the evaluation and follow-up of bone disease in GD , they can be used for specific clinical questions . Alternatively to MRI, ^99m Tc-methylene diphosphonate ( ^99m Tc-MDP) bone scintigraphy can be used for the discrimination of osteomyelitis and avascular necrosis if performed 72 h after clinical onset adding significant information in this setting, since discrimination of these two conditions by clinical means is often difficult or impossible . Further applications of bone scintigraphy include the detection of occult fractures or the evaluation of loosening of hip joint prostheses, in which case 3-phase bone scintigraphy should be applied . Bone marrow scintigraphy indirectly visualises the bone marrow infiltration by Gaucher cells by imaging the extent of bone marrow displacement. The lipophilic tracer ^99m Tc-methoxyisobutyl ( ^99m Tc-MIBI) directly images the glycolipid deposits due to Gaucher cells thus being useful for the quantification of bone marrow infiltration prior to therapy and during follow-up on ERT . Direct imaging of bone marrow infiltration by Gaucher cell deposits by ^99m Tc-MIBI scintigraphy is also of particular interest in children in whom bone marrow undergoes a developmental conversion from red to yellow marrow in the appendicular skeleton . In young GD-patients, MRI interpretation is thus more difficult than in adults in estimating the exact amount and extent of bone marrow infiltration by Gaucher cells . Furthermore, scintigraphy could be used as an alternative to MRI in those patients who cannot undergo MRI imaging (e.g., pacemaker, joint replacements or claustrophobia) and in places with limited access to MRI ( Fig. 5 ).

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