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doi:10.3748/wjg.14.3968

World J Gastroenterol 2008 July 7; 14(25): 3968-3973

World Journal of Gastroenterology ISSN 1007-9327
2008 The WJG Press. All rights reserved.

TOPIC HIGHLIGHT
Yusuf Bayraktar, Professor, Series Editor

Gaucher disease: New developments in treatment and

etiology

Ozgur Harmanci, Yusuf Bayraktar

Ozgur Harmanci, Yusuf Bayraktar, Department of Gastroenterology, Hacettepe University Faculty of Medicine, Sihhiye
06100, Ankara, Turkey
Au t h o r c o n t r i b u t i o n s : Harmanci O and Bayraktar Y
contributed equally to this work.
Supported by Hacettepe University Faculty of Medicine
Correspondence to: Ozgur Harmanci, MD, Department of
Gastroenterology, Hacettepe University Faculty of Medicine,
Sihhiye 06100, Ankara, Turkey. [email protected]
Telephone: +90-312-4439428 Fax: +90-312-4429429
Received: March 31, 2008
Revised: April 12, 2008
Accepted: April 19, 2008
Published online: July 7, 2008

Abstract
Gaucher disease (GD) is an autosomal recessive
disease which if undiagnosed or diagnosed late
results in devastating complications. Because of the
heterozygous nature of GD, there is a wide spectrum
of clinical presentation. Clinicians should be aware of
this rare but potentially treatable disease in patients
who present with unexplained organomegaly, anemia,
massive splenomegaly, ascites and even cirrhosis of
unknown origin. The treatment options for adult type
GD include enzyme replacement treatment (ERT) and
substrate reduction treatment (SRT) depending on
the status of the patient. Future treatment options are
gene therapy and smart molecules which provide
specific cure and additional treatment options. In this
review, we present the key issues about GD and new
developments that gastroenterologists should be aware
of.
2008 The WJG Press. All rights reserved.

Key words: Gaucher disease; Enzyme replacement

treatment; Substrate reduction treatment; Gene
therapy; Liver fibrosis
Peer reviewer: George Y Wu, Professor, Department of
Medicine, Division of Gastroenterology-Hepatology, University
of Connecticut Health Center, 263 Farmington Ave, Farmington,
CT 06030, United States

Harmanci O, Bayraktar Y. Gaucher disease: New developments

in treatment and etiology. World J Gastroenterol 2008;
14(25): 3968-3973 Available from: URL: http://www.wjgnet.
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com/1007-9327/14/3968.asp DOI: http://dx.doi.org/10.3748/

wjg.14.3968

INTRODUCTION
Gaucher disease (GD) is a storage disease in which
macrophage sphingolipidosis accumulation occurs.
This progressive disease results from deficiency of
glucocerebrosidase (acid--glucosidase) in lysosomes.
This enzyme is responsible for cleaving -glycoside into
[1]
-glucose and ceramide subunits . GD is inherited in
an autosomal recessive fashion. The OMIM (Online
Mendelian Inheritance in Man: http://www.ncbi.nlm.
nih.gov/Omim) code for adult type GD is 230800.
It has 2 major forms: non-neuropathic (type 1,
most commonly obser ved type in adulthood) and
neuropathic (type 2 and 3). The disease is characterized
by massive splenomegaly due to excessive accumulation
of glucosylceramide in splenic macrophages. Other
than spleen, so called Gaucher cells are the lipid-laden
macrophages and can be observed in liver and bone
marrow. Therefore GD causes organ damage where
macrophages are densely present. Clinical alterations
in bone, liver and spleen resulting in splenomegaly,
hepatomegaly, hematological changes and orthopedic
complications are the most predominant ones. Rarely
kidney, skin, heart and central nervous system may be
involved.
Recent advances in genetic technology have made
it possible to manage the GD patients with enzyme
replacement treatment (ERT). Substrate reduction
treatment (SRT) is also currently available. In this review,
we will discuss new developments in adult type GD
disease in terms of its etiology and treatment from a
gastroenterologists point of view.

ETIOLOGY AND PATHOGENESIS

The gene coding for the enzyme responsible for GD is
located on chromosome 21. In this single gene, about
200 mutations are defined up to date[1]. Most commonly
observed mutations are N370S, L444P, RecNciI, 84GG,
R463C, recTL and 84 GG is a null mutation in which
there is no capacity to synthesize enzyme. However,
N370S mutation is almost always related with type 1

Harmanci O et al . Gaucher disease

3969

Table 1 Worldwide most common mutations in GD

Population

Most frequently observed

mutations

Frequency of
mutations (%)

Turkish[3]

N370S
L444P

61.80

Japanese[4]

L444P
F2131

55

Taiwanese[5]

L444P
RecNciI

78.50

Czech and Slovak[6]

N370S
L444P
RecNciI

76

N370S,
c.84-85insG IVS2 + 1G-->A L444P

93

Ashkenazi Jews[7]
Hungarian[8]

Spanish[9]

N370S
L444P
RecNciI

70.30

N370S
L444P

68.70

disease and milder for ms of disease. Ver y rarely,

deficiency of sphingolipid activator protein (Gaucher
factor, SAP-2, saposin C) may result in GD. This rare
condition is due to congenital absence of carrier protein
involved in sphingolipid catabolism[2].
Worldwide differences in genetic mutations are
shown in Table 1. Therefore, genetic heterogeneity
results in phenotypic heterogeneity. The phenotypic
presentation of the same mutation may vary in a wide
spectrum. This difference is most possibly related
with ethnicity, genetic background, environmental and
nutritional factors. But most important of all, the exact
pathophysiological mechanisms of GD are not clear yet.
Since the total accumulation of glycosphingolipid in a
massively enlarged spleen constitutes only about 2%,
there must be other unknown pathways that result in
splenic proliferation, activation and enlargement[10]. One
of the most important changes occurs in macrophages.
The accumulation of glycosphingolipid in the lysosomes
of macrophages results in some expected consequences
by unknown mechanisms. One important pathway is
the activation of macrophages. The great majority of
evidence of macrophage activation stems from the
fact that patients with GD have increased levels of
macrophage-derived inflammation related molecules
such as interleukin-1, interleukin-6, interleukin-10 and
TNF-[11,12]. With regard to macrophage activation, these
cytokines might be responsible for some consequences
like increased osteoclastic activity in bones resulting in
osteopenia, osteoporosis and fractures.
Activated macrophages also secrete some other
molecules that can be used as a marker of disease
activity and surveillance. The enzyme chitotriosidase
(CT) and CC chemokine ligand 18 (CCL8) are examples
of these markers. CT is originally a chitinase which is
responsible for degradation of chitin. In humans, CT
playas a role during the remodeling phase of the tissue
healing process and in immune-chemotaxis[13,14]. Previous
studies reported that screening of increased CT activity
can be used as a GD marker[15,16]. But the null allele in

the general population, which is expressed at a mean

frequency of 4%, causes deficiency of the enzyme[17].
The levels of the enzyme may also increase in elderly
people[18] and in other granulomatous diseases such as
sarcoidosis[19]. In addition, other macrophage markers
such as macrophage inflammatory protein (MIP)-1,
MIP-1[20] and soluble CD163[21] can also be used for
surveillance of the disease.

CLINICAL MANIFESTATIONS
In general, GD patients present initially with
hematological abnormalities due to hypersplenism.
Gastroenterologists can be consulted because of
anemia, massive splenomegaly or hepatomegaly of
unknown cause. Although rare, patients presenting
with hepatosplenomegaly and ascites are reported[22].
As mentioned previously, GD involvement changes
in severity according to the density of macrophages
in the particular organ and partially depends on the
phenotypically heterozygous nature of the disease itself.
The most common mutation, N370S, could result
in subtle symptoms and silent disease due to presence
of some degree of enzymatic activity resulting in delays
in diagnosis. The delays in diagnosis eventually results
in irreversible complications. A recent study by Mistry
et al showed that in adult patients with type 1 disease the
average time from first appearance of symptoms of GD
to final diagnosis was 48 mo. In addition, hematologyoncology specialists who were managing two-thirds of
the patients considered diagnosis of GD only in 20%
for the classical symptoms (bone pain, organomegaly
and low blood counts)[23].
The diagnosis of GD is straightforward. The
demonstration of genetically miscoded or absent enzyme
levels is diagnostic. For this purpose, direct analysis of
glucocerebrosidase in peripheral blood leukocytes is
utilized. The activity of glucocerebrosidase is variable in
white cell type[24], enzyme activity usually increases from
granulocytes to lymphocytes to monocytes. Type 1 GD
patients have 10 to 15 percent of the normal enzyme
activity whereas type 2 and 3 patients usually have lower
activity. Due to considerable overlap of enzymatic
activity between heterozygote carriers and normal
individuals, enzyme analysis cannot distinguish GD
carriers from non-GD-carriers. In order to differentiate
the car rier state, the genetic analysis which was
mentioned previously should be applied for definitive
diagnosis.
After diagnosis, GD patients should be classified
according to clinical severity scores. The modified
scoring system developed by Zimran (Zimran severity
score index, ZSSI) [25] should be used during initial
evaluation and during follow up of patients taking
treatment (Table 2).
Gastrointestinal system involvement in GD
In the type 1 GD, gastrointestinal complications such
as hepatomegaly, splenomegaly, cirrhosis, ascites, and
esophageal variceal hemorrhage predominate and
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are well known. However, other associations such as

increased risk of hepatic carcinogenesis and cholelithiasis
are not taken into consideration.
In the literature, there are reports of increased risk
GD associated hepatocellular carcinoma (HCC) [26-28].
In a recent survey, the risk of development of HCC in
GD patients is found to be 141 times more than normal
controls[29]. The overall risk of malignancy (especially
hematological malignancies such as multiple myeloma)
development is known to be increased. However, some
studies suggest that this risk is not different from the
normal population in early and middle age[30].
Patients with GD, especially females over age of
forty are found to be increased in risk of cholelithiasis.
This increased risk is usually attributed to factors like
anemia, prior splenectomy, hepatic involvement and an
increased biliary excretion of glucosylceramide[31,32]. The
management of cholelithiasis is not different from nonGD patients.
The portal hypertension observed in GD has 2
causes. The first is the overflow in the portal system
secondary to splenomegaly which usually resolves
after splenectomy. The second is observed in patients
who already had a splenectomy. In these patients,
massive infiltration of Gaucher cells in the liver
parenchyma results in intrahepatic portal hypertension.
The accumulation of excessive sphingolipid in liver
macrophages (Kupffer cells) might result in activation of
some unknown mechanisms or cell-to-cell interactions
might ensue which eventually results in hepatic fibrosis.
Hepatic fibrosis and eventual cirrhosis is the most
feared complication of GD for liver involvement[33,34].
Although ERT results in reversal of hepatomegaly
to normal, hepatic fibrosis still remains a challenge.
The exact pathophysiological pathways of progressive
hepatic fibrosis are unknown, but progressive fibrosis
is obser ved mostly in pediatric patients. In initial
presentation, hepatic transaminase levels are found to be
elevated in nearly 50% of patients[25].
Other non-specific findings of GD involvement
of the liver are hepatomegaly (detected in 100% of
patients with splenomegaly but detectable only in 87%
of patients with splenectomy), non-specific mass like
lesions in liver, peri-portal and retroperitoneal lymph
nodes[35].
Liver transplantation is rarely necessary compared to
a few decades ago because of the introduction of ERT.
However, development of features of progressive liver
fibrosis such as elevated liver transaminase levels and no
normalization in hepatomegaly despite adequate enzyme
treatment should alert for rapidly developing fibrosis in
a given patient. Liver transplantation should always be an
option in patients with GD. Theoretically, there is a risk
of recurrence of liver disease due to excessive burden
of glycosphingolipid influx more than transplanted liver
can handle. This risk is higher in patients with a spleen;
therefore a splenectomy (if not performed until time
of transplantation) should also be performed when
transplantation is decided.
Despite its rarity, GD may involve other sites of the
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Table 2 Zimran severity score index, 1992 (SSI scores of

0-10: Mild disease; 11-25: Moderate disease; > 25: Severe
disease)
Feature

Detail

Cytopenia

Non-splenectomized
Splenectomized
Leukopenia
Anemia
Thrombocytopenia

None
Mild
Moderate
Massive

0
1
2
3

Splenomegaly

Splenectomy
Hepatomegaly

Score

1
1
1

3
None
Mild
Moderate
Massive

Liver enzymes (aspartate

Normal
aminotransferase, alkaline phosphatase, Some abnormal
gamma-glutamyltransferase, lactate
All abnormal
dehydrogenase)
Signs of clinical liver disease

0
1
2
3
0
1
2
4

CNS involvement

20

Other organ involvement (kidney,

lungs or any other)

Bone disease-objective findings

No signs
X-ray or nuclear scan
abnormality

0
1

Bone disease-objective findings

No pain
Mild pain
Chronic pain unrelated
with fractures

0
2
3

Bone fractures

No fracture
Post-traumatic fracture
Pathologic fracture or
aseptic necrosis

0
1
5

gastrointestinal system other than the liver and spleen.

GD may result in Gaucher cell pseudotumors in
the abdomen resulting in mass like lesions [36,37]. This
phenomenon is very important because GD is related
with increased incidence of cancer but currently, GD
pseudotumors are rare due to ERT. Association of GD
with colonic infiltration of Gaucher cells[38], massive
gastrointestinal bleeding due to ileal involvement[39] and
Menetrier disease of the stomach[40] are also reported.

TREATMENT STRATEGIES IN GD
Pre-treatment evaluation in GD
Since adult GD patients come to attention after
development of symptomatic anemia, organomegaly or
complications such as fractures, indications for specific
treatment of GD are beyond the presence of these
symptoms. The available ERT and SRT options are
expensive (annual cost of ERT is around 1 billion US
dollars[41]) and individual responses for these treatments
are highly variable so that some patients may report
no improvement. Therefore, with parallel to variability
in phenotypic presentation, decision for treatment

Harmanci O et al . Gaucher disease

must be individualized. In our personal practice, severe

organomegaly, high degree of cytopenia, event of
minor bleeding due to thrombocytopenia, bone disease,
liver enzyme elevations with severe organomegaly and
presence of any organ involvement other than liverspleen-bone triad are indications of treatment. The aims
of treatment are reversal of organomegaly, prevention
of complications and increase in quality of life.
ERT
Alglucerase (extracted from human placenta) is the first
enzyme treatment modality for GD patients to provide
specific treatment. Major limitations of this product were
its low degree of reproducibility (because of low number
of available placenta), risk of blood borne infections,
very short half-life (about 4.7 min in blood and 2 h in
visceral organs including liver and spleen)[42,43]. These
limitations had resulted in new research and development
of a recombinant enzyme; imiglucerase. Imiglucerase
is obtained from genetically manipulated ovary cells
of Chinese hamsters. This enzyme has a longer half
life and lack of blood borne infection risk. Despite the
clinical results, imiglucerase looks excellent; there is only
one randomized controlled trial with imiglucerase up
to date. In this study by Schiffmann et al[44], the primary
end-point was the improvement in bone mineral density
of the lumbar spine. ERT (combination of alglucerase
and imiglucerase) was compared with vitamin D and
calcitriol in three patient arms. The total number of
randomized patients was 29. The authors concluded
that ERT alone, or in combination with calcitriol,
cannot repair the bone composition in splenectomized
adult Gaucher patients. They also stated that the ERT
significantly improved hemoglobin, platelet counts, and
liver volume. There are two other randomized trials. The
first one was designed to compare the effectiveness of
imiglucerase vs. alglucerase (15 patients per treatment
arm) which found no significant difference in the two
molecules[45]. The second randomized controlled trial is
a recent study by deFost et al[46] who showed that low
frequency administration of ERT in adult Gaucher type
I patients maintains stable disease in most patients.
Although the number of randomized controlled
trials in ERT does not satisfy clinicians as compared
with other conditions, this currently available treatment
option remains unique. The other option of treatment is
substrate reduction therapy (SRT) and has a limited field
of clinical use.
SRT
The idea underlying SRT is the inhibition of formation
o f s p h i n g o l i p i d s t h a t a c c u mu l a t e d u r i n g G D.
N-alkylated imino sugars are the prototype of this
treatment. N-butyl-deoxynojirimycin (NB-DNJ) or
miglustat is used on GD to reduce the formation of
glucosylceramide by inhibiting the glucosylceramide
synthase enzyme[47]. There are various studies related
to efficacy of SRT, which showed improved blood
counts, decrease in volumes of liver and spleen and
increased quality of life[48,49]. One recent study showed

3971

comparable results with ERT[50]. The most important

advantages of SRT are its oral administration (ERT is
given as intravenous administration over several hours
and must be repeated in 2-3 wk intervals), low costs and
availability. Major drawbacks of SRT are safety issues.
Theoretically, long term inhibition of glycosphingolipid
inhibition may result in detrimental results but no major
adverse reaction is reported up-to-date. Minor adverse
reactions are weight loss, mild tremor, diarrhea, and
gastrointestinal upset. In patients who received previous
ERT, switch to SRT is well tolerated[51]. SRT is currently
limited only to adult type 1 patients who can not tolerate
ERT.

THE FUTURE OF GD THERAPY

Gene therapy
The administration and incorporation of a healthy
genome replacing a deficient genome appears to be the
cure for GD. There are a few studies in the literature
investigating this possibility. In early animal models of
gene therapy the vectors responsible for infecting
a healthy genome were vir uses (adeno-associated
virus, lentivirus and retrovirus). These studies showed
promising results for the future [52-54] . Neither ERT
nor SRT have achieved excellent results in ter ms
of neurological and pulmonary involvement due to
problems such as inability to pass through the bloodbrain barrier. The advantage of gene therapy is its
widespread infection of specific targeted cells in the
body substantially increasing the enzyme levels to a
considerable level.
Chaperone treatment
The ability of imino sugars to increase the strength
of the target enzyme (glucocerebrosidase) is shown
previously by Sawkar et al in a study[55]. These chemicals
increase the half life of the enzyme by inhibiting its
degradation and by providing stabilization. Although this
option currently does not seem to offer a monotherapy
option, chaperones might be an option for combination
treatment strategies.

CONCLUSION
Adult type GD is a heterozygous disease. Because of
vulnerability to delayed diagnosis, timely diagnosis
and early initiation of appropriate therapy are crucial
and prevent detrimental complications and stops the
progression of disease to some extent. In the future,
it might be possible to cure this genetic disease by
gene-vaccines. Therefore, we require more investment
on investigations for gene therapy. ERT and SRT have
undeniable therapeutic effects, but there seems to be
need for more evidence before putting them into goldstandard therapy for all patients.

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