Rare but important haematologicalconditions: Gaucherdisease

1. RARE CONDITIONS
Rare but important
haematological conditions:
Gaucher disease
Derralynn Hughes
Abstract
Gaucher disease is a rare autosomal recessive disorder of sphingolipid
metabolism. Deficiency of b-glucocerebrosidase results in accumulation
of glucosylceramide in cells of the reticuloendothelial system, with conse-quent
organomegaly and bone marrow failure. Recent research has
suggested that defects exist beyond the macrophage, for example, in
immune and mesenchymal-derived cells. Patients often present to haema-tologists
and, despite the availability of an enzyme assay, diagnosis is
often made on bone marrow biopsy. Specific therapy is available by
enzyme replacement or substrate reduction, resulting in improvement
of haematological parameters and bone disease. Patients with Gaucher
disease suffer a higher incidence of haematological malignancy but the
pathology underlying this is not understood, nor is it known whether
the risk is reduced by long-term Gaucher-specific therapy.
Keywords Gaucher; enzyme replacement therapy; macrophage;
substrate reduction therapy
Introduction
Gaucher disease (GD) is an autosomal recessive disorder due to
deficiency of b-glucocerebrosidase and accumulation of gluco-sylceramide
in cells of the reticuloendothelial system (Figure 1).
The gene coding for b-glucocerebrosidase (GBA1) is located on
chromosome 1q21 and approximately 300 mutations of the GBA1
allele have been reported.1 The reported incidence of GD is
1:57,000 but GD is more common in Ashkenazi Jews, in whom the
incidence is 1:900e1:1225, and carrier frequency 1:10e1:17.5.2
Haematological presentation
Clinically GD is divided into non-neuronopathic (type 1) and
neuronopathic (types 2, 3) types. Type 1 GD is the most prevalent
and presents with clinical features related to the effects of
What’s new?
C Recent research has suggested defects exist beyond the
macrophage such in immune and mesenchymal-derived cells
C Delays in initiation of therapy appear to impact on the likeli-hood
of avascular necrosis
C Therapy is available by enzyme replacement, of which there are
now three forms available, and oral substrate reduction with
one therapy available and one in development
substrate accumulation in macrophages, including fatigue, easy
bruising, anaemia and bone pain3 The most common laboratory
feature at presentation is thrombocytopenia due to splenomegaly
in combination with bone marrow infiltration. Data from the
International Collaborative Group on Gaucher Disease registry
shows a median platelet count in non-splenectomized patients of
85 109/litre.4 Low platelets combined with abnormalities of
platelet function result in a bleeding tendency, which may be
spontaneous or become obvious during dentistry, surgery, or at
parturition5 A variety of coagulation factor deficiencies including
acquired von Willebrand’s disease have also been described,6 and
might in part be due to low grade disseminated intravascular
coagulation or, in the case of factor XI genetic deficiency, asso-ciated
with Ashkenazi heritage.
Severe anaemia at presentation is less common and suggests
more severe bone marrow infiltration by glucosylceramide-laden
Gaucher macrophages. Iron and B12 deficiency and autoimmune
haemolysis have also been described.7 Fatigue is often out of
proportion to the haemoglobin concentration and is likely to be
multifactorial in the context of a generalized inflammatory state
and cachexia in the most severe cases.8
Splenomegaly is common and may result directly in abdom-inal
pain or early satiety. The enlarged spleen may be massive
and contain circumscribed accumulations of Gaucher cells
(Gaucheroma) (Figure 2)9 Hepatomegaly is usually less marked
but in severe cases cirrhosis can occur and a number of cases of
hepatic transplantation have been reported.10 Abdominal pain
may also be due to gallstones, which are more frequent espe-cially
in splenectomized patients.11
Bone disease
The majority of patients have radiographic evidence of bone
involvement with features that include local or generalized
osteopenia, osteosclerosis, infarction, remodelling abnormalities,
such as the Erlenmeyer flask deformity, and fractures.12 Patients
experience severe episodes of localized bone pain with raised
inflammatory markers and sterile blood cultures (bone crises) on
a background of chronic pain and disability. Spontaneous frac-tures
may occur and many patients require early joint replace-ment.
The aetiology of osseous manifestations is not completely
understood. Raised pressure in the marrow compartment due to
excess storage cells causing vascular occlusion may contribute to
infarction and avascular necrosis. However, remodelling abnor-malities
and reduced bone density are likely to be more complex,
involving abnormalities of osteoblast and osteoclast lineages.13
Several small cohort and large database studies have indicated
an increased risk of malignancy, particularly haematological, in
Derralynn Hughes MA DPhil FRCP FRCPath is a Senior Lecturer in Haema-tology
at the University College London, UK, and has clinical respon-sibilities
in the area of haematology and lysosomal storage disorders.
Major laboratory projects are currently aimed at understanding the
pathophysiology underlying Gaucher-related bone pathology, the
increased incidence of malignancy in Gaucher’s disease and phenotypic
variation in AndersoneFabry disease. Dr Hughes has a clinical research
commitment and is actively involved in a number of trials examining
the efficacy of enzyme replacement therapy and other new therapies in
the treatment Gaucher’s, Fabry’s and Pompe’s disease, and muco-polysaccharide
(MPS) disorders. Conflicts of interest: DH has received
research and travel grants, honoraria for speaking and consultancy fees
from Shire HGT, Genzyme/Sanofi, Actelion and Protalix/Pfizer.
MEDICINE 41:4 252 2013 Elsevier Ltd. All rights reserved.

2. RARE CONDITIONS
GD. The risk of multiple myeloma has been suggested to be up to
50 times the background rate. The reason for this remains
unclear.14,
Diagnosis
A recent retrospective analysis of referral routes to a UK
specialist centre found that, despite the availability of specific
therapies for GD, there are still significant delays between onset
of symptoms and diagnosis. In most patients, GD is diagnosed by
haematologists, usually by bone marrow trephine biopsy.15 This
is probably a haematological default pathway for patients pre-senting
with splenomegaly and cytopenias and results in inci-dental
finding of bone marrow Gaucher cells. However, there is
a differential diagnosis for Gaucher cells (Table 1).
The diagnosis of GD must therefore be confirmed by finding of
reduced b-glucocerebrosidase enzyme activity. This is a simple
fluorometric assay that can be performed on leucocytes from
whole blood, cultured fibroblasts (rarely necessary) or blood
spots.16 Raised awareness of the condition and the availability of
this assay may expedite diagnosis and avoid the need for bone
marrow biopsy. Sequencing of the glucocerebrosidase gene
allows definition of the pathogenic mutations, which can assist in
prognostication and genetic counselling, but is not essential for
diagnosis.
Assessment and monitoring
Following diagnosis, patients should be assessed for the extent
and severity of their symptoms. MRI of the axial skeleton
provides information on the degree of bone marrow infiltration
and skeletal abnormalities, including bone infarction/avascular
necrosis and remodelling abnormalities.17 Bone density should
be assessed using DXA. In a limited number of centres, quanti-tative
chemical shift imaging (QCSI) reveals the percentage bone
marrow fat, an indicator of bone complications.18 Several scoring
systems have been developed, more recently incorporating
quantitative assessments of organ volume and bone disease.19
The utility of a number of biomarkers correlating with baseline
disease severity and treatment effects has been evaluated. The
activity of serum chitotriosidase enzyme is increased in GD
patients.20 Other markers found elevated include tartrate-resistant
acid phosphatase, angiotensin-converting enzyme, and
MIP1a and b.21
Therapy
Intravenously administered enzyme replacement therapy (ERT)
has been shown to be safe and effective in improving clinical
features and health related quality of life in GD. Currently, there
are three recombinant enzyme formulations, distinguished by
the cell lines from which they have been generated: imiglucerase
(CHO cells; Genzyme/Sanofi); velaglucerase (human cells; Shire
HGT); and taliglucerase (carrot cells; Pfizer/Protalix available
in the USA and Israel). Before the availability of ERT, palliative
splenectomy was undertaken but has been associated with
significantly more severe bone disease and a higher risk of long-term
complications such as multiple myeloma.22 Oral substrate
reduction therapy is an alternative approach, based on partial
inhibition of substrate synthesis, as a means of reducing
substrate burden to match the residual activity of the mutant
enzyme. Miglustat, an iminosugar, is the first oral treatment and
a second agent, eliglustat, is currently the subject of clinical
trials.23,24
Figure 1 Glucosylceramide engorged macrophage.
Figure 2 MRI scan of liver and spleen of 55-year-old man with Gaucher’s
disease demonstrating enlargement of the liver and spleen with multiple
focal mass lesions.
Differential diagnosis of ‘foamy’ macrophages in the
bone marrow
Lysosomal storage
disorders
Haematological disorders
(pseudo-Gaucher cells)
Gaucher disease
Fabry disease
GM1 gangliosidosis
Wolman/cholesterol ester
storage disorder
NiemannePick A and B
(sea blue histiocytes)
Multiple myeloma
Hodgkin’s lymphoma
Non-Hodgkin’s lymphoma
Chronic myeloid leukaemia
myelodysplasia
B cell acute lymphoblastic
leukaemia
Thalassaemia
Sickle cell disease
Table 1
MEDICINE 41:4 253 2013 Elsevier Ltd. All rights reserved.

3. Conclusion
Gaucher disease is a rare but treatable metabolic condition with
a wide range of haematological and osseous manifestations.
Patients still experience delays in diagnosis, and delays in initi-ation
of therapy appear to impact on the likelihood of ongoing
bone complications.25 Gaucher disease should therefore be
considered in the differential diagnosis for a patient presenting
with unexplained thrombocytopenia, anaemia or splenomegaly
with or without accompanying bone pain. A
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Practice points
C Although Gaucher’s disease is a rare metabolic disorder it
often presents first to haematologists
C Patients display symptoms of bone marrow failure, hep-atosplenomegaly
and bone pathology and have a higher inci-dence
of haematological malignancy especially myeloma
C Early diagnosis and assessment may facilitate supportive care
and the initiation of Gaucher-specific therapy in appropriate
individuals, and may reduce the potential for long-term
disabling complications
RARE CONDITIONS
MEDICINE 41:4 254 2013 Elsevier Ltd. All rights reserved.