Am J Clin Pathol 2013;140:91-96 91
91 DOI: 10.1309/AJCPFVSAEGO67NGT 91
© American Society for Clinical Pathology
Anatomic Pathology / Gaucher Femoral Head Histology After ERT
Histologic Findings of Femoral Heads From Patients
With Gaucher Disease Treated With Enzyme Replacement
Ehud Lebel, MD,1 Deborah Elstein, PhD,2 Ariel Peleg,2 Constantine Reinus, MD,3 Ari Zimran, MD,2
and Gail Amir, MBChB4
Key Words: Gaucher disease; Gaucher cells; Bone histology; Enzyme replacement therapy; Osteonecrosis
A b s t r a c t
Objectives: To assess correlations of patient
demographics, including enzyme replacement therapy
(ERT) with bone histology, to facilitate decisions of
whether and when to perform hip replacement surgery
in patients with Gaucher disease.
Methods: We examined the histology of surgically
removed femoral heads and categorized findings by the
presence or extent of osteonecrosis, Gaucher cell (GC)
infiltration, and bone regeneration qualifiers using a
tripartite histology-based scoring system.
Results: Twenty-two patients with 26 bone
specimens were evaluated. Seventeen patients (77%)
were splenectomized, 16 (73%) received ERT, and 12
(55%) had the putatively milder genotype (N370S/
N370S), with the rest putatively at increased risk
for skeletal disease (N370S/other). The 3 histology
subscores were applicable to all specimens.
Osteonecrotic bone was seen in 19 of 26 (73%);
osteoarthritis was seen in all cartilage specimens.
Gaucher cell infiltration was not correlated with
demographics or disease severity. A trend was noted
between reduced GC infiltration and ERT (r = 0.407),
but regeneration qualifiers were not correlated with
ERT or other features.
Conclusions: Histologic findings of GC infiltration
and bone regeneration qualifiers did not correlate
with demographics or with exposure to ERT. Most
specimens unexpectedly showed good regenerative
responses to osteonecrosis despite heavy GC
Gaucher disease, possibly the most prevalent lyso-
somal storage disease, is caused by a hereditary deficiency
in the activity of b-glucocerebrosidase, one of the lysosomal
enzymes required for glycolipid degradation.1 Deficiency
results in the accumulation of glucocerebroside in cells of the
monocyte-phagocyte system (Gaucher cells [GCs]), notably
in the spleen, liver, and bone marrow.
Bone manifestations are an important cause of morbid-
ity and may occasionally be the presenting symptom of
the disease. Frequently encountered skeletal complications
of Gaucher disease include the asymptomatic Erlenmeyer
flask deformity and some degree of osteopenia2 but also
varying degrees of chronic and acute bone pain. Less com-
mon manifestations of bone involvement include cortical
thinning, osteonecrosis, osteosclerosis, fractures due to low
bone density, height retardation in children, and, rarely, acute
Osteonecrosis is a complication of Gaucher disease that
affects mainly the femoral head but also may have an impact
on other bones such as the proximal humerus, tibia, and ver-
tebral bodies. The long-term results are joint collapse and sec-
ondary osteoarthritis. Osteonecrosis in this context is thought
to arise from a combination of increased bone marrow pres-
sure due to infiltration by GCs, vascular alterations including
thrombosis, and/or activation of proinflammatory cytokines.4
The management of osteonecrosis includes orthopedic
interventions and disease-specific enzyme replacement ther-
apy (ERT).5 Drilling (core decompression) the juxta-articular
bone in the early stages of osteonecrosis was attempted to
encourage repair and to prevent subchondral collapse and
subsequent osteoarthritis6; however, the long-term outcome
showed no such benefit.
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96 Am J Clin Pathol 2013;140:91-96
96 DOI: 10.1309/AJCPFVSAEGO67NGT
© American Society for Clinical Pathology
Lebel et al / Gaucher Femoral Head Histology After ERT
some patients, osteonecrosis was confined to 1 site, but in
one-half of the patients, there were other sites as well (ie, hip
degeneration was not necessarily the first or only catastrophic
bone event in some, but this too was not correlated with any
demographic or disease-specific parameter or ERT experi-
ence). Thus, our findings seem to indicate that osteonecrosis
in Gaucher disease has no defining or predictive features.
There was a rapid onset of AVN (before age 17 years) in
patient 19, who had an intact spleen and was receiving ERT,
albeit erratically, for a few years, whereas in other patients,
there was a correlation between the onset of the osteonecro-
sis and prior splenectomy (patient 16 was splenectomized
in 1992 and showed early evidence of AVN in 1994). Six
patients underwent THR when they were not receiving ERT
(all received ERT thereafter), but in patient 1, introduction of
ERT did not prevent osteonecrosis in the contralateral hip. On
the basis of the histologic scores and the lack of normalization
of bony architecture with ERT as illustrated here, we believe
that osteonecrosis cannot be prevented by ERT. An example
is shown in patient 4, who, despite relatively high doses of
ERT and an excellent hematologic and visceral response
within 1 year, had osteonecrosis that rapidly advanced into
femoral head collapse.
With regard to the claim that bone invaded by GCs is
inert,8 this was not our experience. In fact, evidence of vary-
ing stages of bone regeneration or healing was seen in 25 of
26 specimens examined, and a high score in 1 or more of
the histologic parameters of healing (2+ or 3+) was seen in
21 of 26 specimens. Thus, our findings shed new light on
the reparative capacity of Gaucher bone despite massive GC
infiltration and evidence of osteonecrosis.
In conclusion, we present a number of patients with
diverse clinical characteristics of Gaucher disease who even-
tually underwent THR for pain because of osteonecrosis of
the hip. No overt unifying variable suggests that these par-
ticular patients were at risk for osteonecrosis. We introduce a
histologic scoring system with 3 categories that respectively
document the destructive process, the degree of GC infiltra-
tion, and the (potential) degree of bone healing. There was no
correlation between the degree of GC infiltration and other
Gaucher-specific measures. The lack of a clear-cut effect of
ERT on the density of GC infiltration is also remarkable and
underscores the need to offer THR to patients based on pain
and functionality, as with other persons, and not await ERT.
Importantly, we believe that we show for the first time the
dynamic, unexpected nature of Gaucher bone. Evidence of
live healthy bone in the matrix (and context) of osteonecrosis
and arthritic changes that are not significantly correlated with
disease features or ERT use leads us to a new understanding
of Gaucher bone in situ.
From the 1Department of Orthopedic Surgery, 2Gaucher Clinic,
and 3Department of Pathology, Shaare Zedek Medical Center,
Jerusalem, Israel, and the 4Department of Pathology, Hadassah
Medical Center, Ein-Karem, Israel.
Address reprint requests to Dr Elstein: Gaucher Clinic/
Shaare Zedek Medical Center, PO Box 3235, Jerusalem 91031,
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