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

RARE CONDITIONS

Rare but importanthaematological conditions:Gaucher diseaseDerralynn Hughes

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

AbstractGaucher 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

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

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

� 2013 Elsevier Ltd. All rights reserved.

Figure 1 Glucosylceramide engorged macrophage.

Differential diagnosis of ‘foamy’ macrophages in thebone 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

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

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.

MEDICINE 41:4 253

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

� 2013 Elsevier Ltd. All rights reserved.

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

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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� 2013 Elsevier Ltd. All rights reserved.