Pathophysiology of skeletal manifestations of type 1 Gaucher’s disease
description
Transcript of Pathophysiology of skeletal manifestations of type 1 Gaucher’s disease
P. LafforgueCHU Sainte-Marguerite,
Marseille, France
Pathophysiology of skeletal manifestations of type 1 Gaucher’s
disease
• Main cause of pain and disability• Most are irreversible
• Most effective treatment should be prevention.
• Bone marrow infiltration• Pain• deformity• Osteonecroses– Acute bone crises /medullary infarcts– Epiphyseal osteonecroses
• Osteolysis• Osteopenia/osteoporosis• Osteomyelitis• Growth retardation• (multiple myeloma)
• Fractures
Deformities
• Erlenmeyer flask
• 60-80% prevalence• Non specific• Impairment of modeling
of dia-metaphyses during growth
Faden MA et al. Am J Med Genet A. 2009; 149A: 1334-45
≈ 33% of patients
• Femoral and humeral heads mainly
• Classical presentation …
• Chronic pain• disability• Joint replacement
Crises: 20-33%Rx: 25%
• Various locations ++• Femurs• Tibiae• Pelvic bones, vertebrae …
• Osteomyelitis-like crises
Epiphyseal ON Medullary infarcts
OSTEONECROSES
Gaucher osteonecroses hallmark« classical » ON
• = idiopathic or secondary (CTC, OH,…)
• « cold »: initially asymptomatic• Occur simultaneously
• In fatty areas :• Epiphyses and metaphyses of long
bones
« rich marrow» ON• = sickle cell, Gaucher, leukemias• « hot »: pseudo-osteomyelitis• Bouts of acute crises, at any time
• In hematopoïetic/invaded areas:• anywhere, extensive
Bone vasculature
Pathophysiology
isch
eam
ia
Vessels lesions
Vessels obturation
extrinsic vessels compression
Bone
/mar
row
nec
rosi
s
Vascular lesions ?100 patients– CCL4/MIP-1β– CCL2/MCP-1– CXCL8/IL-8 +++– CCL18/PARC– CCL5/RANTES +++
• in Gaucher vs controls• in Gaucher ON vs ON free• Especially when ON occurs during ERT
Limits!Treated patients, assessment distant from ON initiationBiological markers of disease activityNo evidence of causality
Pavlova, Blood Cells Mol Dis 2010
Vascular obturation
Micro-emboli of lipidic particles: corticosteroids dyslipidemia alcoholism
thrombosis sickle cell clotting abnormalities
Gas bubbles: dysbaric ON
Idiopathic ON• 25 à 30% of ON• 40-50 years-old males
Thrombophilia:
S protein deficiencyactivated C protein resistanceProthrombin gene mutationsFactor V Leidenanti-phospholipid Ab
thrombolysis:
HyperhomocysteinemiaMTFR gene mutation lipoprotein(a) tPaiApo B
Limits:• High prevalence in general
population• High diversity of disorders
• Inconsistency across studies• Lack of appropriate control
groups
Extrinsic vascular compression
extra-vascular components vascular space
Adipocytic hypertrophy CTC OH dyslipidemia
Marrow edema ischaemia: vicious circle
intra-medullary hemorrhages? m. de Gaucher
Medullary hypertrophy Gaucher’s disease sickle cell
Marrow gas bubbles dysbaric ON
Hématopoietic cells
Bone trabecule
capillary
adipocyte
Risk factors for ON in GDLitterature:• correlated with marrow infiltration• splenectomy ++• male• with ERT Rodrigue, Clin Orthop 2009; Mistry, BJH 2009
ICGG Registry: 544 GD with ON compared with 2008 GD without ON:• Slightly more anemia ( 21,5% vs 11,9%)• Slightly more N270S heterozygoty• Slightly more splenectomy (31% vs 24%), NS
Khan A, JBMR 2012 e-pub
56 type 1 GD 24 with / 32 without ON: strong association of ON with:• Younger age at diagnnosis • Any other bone manifestation• splenectomy Lanfranchi-Debra 2012, unpublished
Natural course of epiphyseal ON
Cell death (osteocytes, marrow cells, adipocytes)
Demarcation by a fibrovascular rim, intra-lesional remodelling
collapse
Subchondralfracture
Natural course
1) ON are definitive
2) Their volume is fixed
3) The key event is subchondral fracture
Natural course
4) Local prognosis depends on residual mechanical properties of the femoral head.
Small ON (<10%)Weight bearing areapartially preserved
Large ON (>20%)Weight bearing area
totally affected
No symptomGood prognosis
Subchondral fractureDeformity
Chronic pain
X-rayMRI +++
osteolysis
• No or few symptoms• At risk for fracture
Osteopenia
• BMD is lower in Gaucher patients Z-score ≈ - 1 SD
• However, moderately:adults: T-score < -2.5: 10/57 (18%)
• BMD diminution is associated with splenectomy, hepatomegaly, N370S genotype Pastores, JBMR 1996
Wenstrup, JBMR 2007
Javier, Osteoporosis International 2010
Pathophysiology of osteopenia:GBA1-deficient mouse model
Mistry PK et al. PNAS 2010; 107 : 19473-8
Lower BMD ↘ stromal cells proliferation ↘ OB differentiation (through PKC inhibition) Unaffected OC activity
Pathophysiology of osteopenia:
Role of• cytokines: IL-1β, IL-6, IL-10, TNFα ?• Minor lipid LysoGL-1?• Also look for classical risk factors
Michelakakis, Biochim Biophys Acta 1996; Allen , QJM 1997; Hollack, Blood Cells Mol Dis 1997
1.Fiore, JBMR 2002; 12 patients2.Ciana, J Inherit Metab Dis 2005; 12 patients3.Drugan, Blood Cells Mol Dis 2002; 16 patients4.Van Dussen, J Clin Endocrinol Metab 20011; 40 patients
• Formation: ↘1,2,3,4
• Resorption: ↗1,2 , ↘3 or Nl4
PERIPHERAL FRACTURES
• 14-20%
• In focal osteolytic areas (pathological fractures )
Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010
T6
T9
VERTEBRAL FRACTURES • 8-21% of patients
VERTEBRAL FRACTURES • Association with low BMD: logical but no firm evidence• Not associated with splenectomy• Associated with overal skeletal burden
Katz, Spine 1993; Stirnemann, Rev Med Int 2006; Javier, Osteoporosis Int 2010
Khan A, JBMR 2012 e-pub
Pathophysiology is largely unknown, but is clearly driven by medullary infiltration!
• Improvement with ERT or miglustat:– Of pain– Of bone crises number– Of BMD
• Few or no new ON:ICCG Registry : follow-up of 2700 Gaucher patients without prevalent ON– ERT initiated < 2 years after diagnosis : ON incidence = 8,1/1000 pts.yrs– ERT initiated > 2 years after diagnosis : ON incidence = 16,6/1000 pts.yrs– Risk x 2 when history of splenectomy
Charrow, Clin Genet 2007Sims, Clin Genet 2008Mistry, Br J Haematol 2009
• However complications may still occur under therapyStiernemann, Arthritis Res Ther 2010
• Open prospective trial• 33 patients (M=43 years) ERT-naive treated with imiglucerase
Bone pain
Lumbar BMD
ostéocalcinBALP
DPyruNTXu
Bone markers
Sims et al, Clin Genet 2008
FN BMD
Children• ICGG Registry • 884 chidren receiving ERT , 8 years follow-up
– height: Z-score -1,4 normal (-0,3)– 90 patients with prevalent bone crises : 0 crises after2 years therapy– 440 patients without prevalent bone crises 2,5% with subsequent new crises– BMD: Z-score -0,35 +0,29 SD
• Fig1, 6 et 7
Andersson et al. Pediatrics 2008
height
New crises
Lumbar BMD