Cacoub p hcv meh 2014
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Transcript of Cacoub p hcv meh 2014
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Extrahepatic Manifestations of Hepatitis C Virus Infection
Pr Patrice CACOUB
Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie CurieCentre National de Référence Maladies Auto-immunesHôpital La Pitié-Salpêtrière, Paris, FRANCE
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Manifestation certainly associated with HCV
%
Vasculitis (PAN, cryoglobulinemia) 5-40 Arthralgia-myalgia 25-35 Sicca syndrome 10-25 Auto-antibodies 10-40 Thrombocytopenia 20-40 Lymphoma RR=35
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• Hepatitis • Cirrhosis• Hepatocarcinoma
• Cryoglobulinemia• Auto-Ab• B-NHL
HepatocyteChoo. Science 1989
LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993
Hepatitis C Virus Chronic Infection:More Than One Target Cell
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Cryoglobulinémies mixtes
Saadoun, Arch Intern Med, 2006
Infection VHC +++
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VASCULARITES: CLASSIFICATIONVASCULARITES: CLASSIFICATION
Chapel Hill, révisé en 2012
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Ferri C et al. Orphanet J Rare Dis 2008Brouet J et al. Am J Med 1974
Les cryoglobulines sont des Immunoglobulines qui précipitent à une température < 37°C et se
dissolvent lors du réchauffement
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Endothelial cells
Cryoprecipitation
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Pathogenesis of
cryoglobulinae
mic vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
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Skin Purpura
Membrano-proliferative Glomerulonephritis CNS Vasculitis
Neuropathy
Cryoglobulinemia Vasculitis
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Distal Polyneuropathy 80%
Cacoub P et al, AIDS 2005
Mixed Cryoglobulin and Neuropathy
• Chronic progressive course, • Distal, symetric, axonal PN, mainly sensory• Few extra neurological signs : purpura• Severe liver involvement• Moderate inflammatory syndrome
MononeuropathyMultiplex 20%
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Cryoglobulinemic Membrano-Proliferative Glomerulonephritis
Doubles Contours
Pseudo-thrombi
GNMP de type 1
IgG/IgM
Kappa/lambda
C3 ±C1q
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HCV Mixed Cryoglobulinemia and Digestive Tract
Mesenteric artery stenosis
Intestinal wall thickening
Terrier B et al, GUT 2011
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Cardiac Involvement in HepatitisC Virus-Related Vasculitis
Terrier B et al, Am J Cardiol 2013
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Central Nervous System Involvement in HCV-
Cryoglobulinemia Vasculitis
HCV-vasculitis HCVControls
(n=40) (n=11) (n=36)--------------------------------------------------------------------------------------Gender (F/M) 23/17 6/5 20/16Age (yrs) 59 ± 13 56 ± 10
58 ± 12WMHS 7.0 ± 9.9 0.9 ± 1.8 *2.0 ± 3.1
PVHS 2.5 ± 3.1 0.4 ± 0.5 * 0.8 ±
1.4
NCFD 2.2 ± 1.8 0.9 ± 0.8 * -
--------------------------------------------------------------------------------------* P<0.01WMHS: White Matter Hypersignals PVHS: Periventricular HypersignalsNCFD: Number of Cognitive Function Deficiency
Casato M et al, J Hepatol 2004
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Age at disease onset 54 ± 13 (29-72) Female/Male ratio 3 Purpura 98% Weakness 98% Arthralgias 91% Arthritis (non-erosive) 8% Raynaud's phenomenon 32% Sicca syndrome 51% Peripheral neuropathy 81% Renal involvement 31% B-cell non-Hodgkin's lymphoma 11% Hepatocellular carcinoma 3%
Features of Mixed Cryoglobulinemia
n=250 Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009
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- important peri-vascular infiltrate of lymphocyte- around small vessels i.e. venules, capillaries- no PMN, no destruction of the vascular wall
Mixed Cryoglobulin and Distal Polyneuropathy
Peripheral Nerve Biopsy
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HCV Core Protein in Skin Vascular Structures
Who’s the culprit ?
Cellular Infiltrate in HCV-Vasculitis
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Detection of Genomic Viral RNA in Nerve and Muscle of Patients with HCV
Neuropathy
Inflammatory vascular lesions in 26/30 (87%) patients
Positive-strand genomic HCV RNA detected in 10/30 patients (muscle 9, nerve 3)
Negative-strand replicative HCV RNA never detected
--> HCV neuropathy probably results from virus-triggered immune-mediated mechanisms rather than direct nerve infection and in situ replication
Authier JF et al, Neurology, 2003
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Rationale for Rituximab treatment in cryoglobulinemic vasculitis
Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
A Role for B Cell Immunity in HCV-Vasculitis
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J Immunol, 2011
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Expansion des Lympho B CD21-/low CD27+ IgM+ chez les patients VHC-MC
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Biais de répertoire des Lympho B CD21-/low CD27+ IgM+ avec expression préférentielle de la chaîne lourde
d’Ig VH1-69
Terrier B. et al. J Immunol 2011
Accumulation de mutations somatiques témoignant de la maturation d’affinité
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Etude de l’apoptose et de la prolifération
Apoptose (expression annexine V) Prolifération (incorporation 3H)
Les LymphoB CD21-/low CD27+ IgM+
sont des cellules anergiques