Extrahepatic Manifestations of
Hepatitis C Virus Infection
Pr Patrice CACOUB

Service de Médecine Interne, et CNRS UMR 708...
Manifestation certainly associated with HCV

%
 Vasculitis (PAN, cryoglobulinemia)

5-40

 Arthralgia-myalgia

25-35

 ...
Hepatitis C Virus Chronic Infection:
More Than One Target Cell
Hepatocyte
Choo. Science 1989

• Hepatitis
• Cirrhosis
• He...
Cryoglobulinémies mixtes
Infection VHC +++

Saadoun, Arch Intern Med, 2006
VASCULARITES: CLASSIFICATION

Chapel Hill, révisé en 2012
Les cryoglobulines sont des Immunoglobulines
qui précipitent à une température < 37°C et se
dissolvent lors du réchauffeme...
Cryoprecipitation

Endothelial cells
7
Pathogenesis of
cryoglobulinaemic
vasculitis

Roccatello, D. et al. Nephrol. Dial. Transplant. 2004

8
Skin Purpura

Neuropathy

Cryoglobulinemia Vasculitis

Membrano-proliferative
Glomerulonephritis

CNS Vasculitis

9
Mixed Cryoglobulin and Neuropathy
Distal Polyneuropathy 80%
• Chronic progressive course,
• Distal, symetric, axonal PN, m...
Cryoglobulinemic Membrano-Proliferative
Glomerulonephritis
GNMP de type 1

Doubles Contours

Pseudo-thrombi

IgG/IgM
Kappa...
HCV Mixed Cryoglobulinemia and Digestive Tract
Mesenteric artery stenosis

Intestinal wall thickening

Terrier B et al, GU...
Cardiac Involvement in Hepatitis
C Virus-Related Vasculitis

Terrier B et al, Am J Cardiol 2013
14
Central Nervous System Involvement
in HCV-Cryoglobulinemia Vasculitis 
HCV-vasculitis HCV

Controls

(n=40)
(n=11)
(n=36)
...
Features of Mixed Cr yoglobulinemia
Age at disease onset
Female/Male ratio
Purpura
Weakness
Arthralgias
Arthritis (non-ero...
Mixed Cryoglobulin and Distal Polyneuropathy

Peripheral Nerve Biopsy

- important peri-vascular infiltrate of lymphocyte
...
Cellular Infiltrate in HCV-Vasculitis

Who’s the culprit ?

HCV Core Protein in Skin Vascular
Structures
18
Detection of Genomic Viral RNA in
Ner ve
and Muscle of Patients with HCV
Neuropathy

 Inflammatory vascular lesions in 26...
A Role for B Cell
Immunity
in HCV-Vasculitis
Rationale for
Rituximab treatment
in cryoglobulinemic
vasculitis

Roccatello,...
J Immunol, 2011
Expansion des Lympho B CD21-/low CD27+ IgM+
chez les patients VHC-MC
Biais de répertoire des Lympho B CD21-/low CD27+ IgM+
avec expression préférentielle de la chaîne lourde
d’Ig VH1-69

Accu...
Etude de l’apoptose et de la prolifération
Apoptose (expression annexine V)

Prolifération (incorporation 3H)

Les LymphoB...
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Cacoub p hcv meh 2014

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  • Diagnosis of neuropathic pain requires identifying the nerve structures that are involved. Pattern recognition is a common means of identifying the location of the deficit. Once the pattern of involvement is recognized, the next step is to identify the etiology.
    Mononeuropathies are usually posttraumatic or caused by entrapment neuropathies.1 Occasionally systemic disease (eg, diabetes or vasculitis) can produce a mononeuropathy.2
    Mononeuropathy multiplex means that a patient has multiple mononeuropathies, usually asymmetric and involving multiple parts of the body. Causes include vasculitis, sarcoidosis, and inflammatory polyneuropathies.2
    Involvement of most of an extremity in the neuropathic process suggests involvement of the plexus, or a plexopathy.2,3 Common causes include trauma, cancer, radiation, and some systemic illnesses.3
    Peripheral polyneuropathy, resulting in a “stocking-and-glove” pattern, is perhaps the pattern most easily recognized.4 It is always the result of a systemic process, such as a toxic exposure, diabetes, or alcohol.1
    1.Boulton AJM, Malik RA. Diabetic neuropathy. Med Clin North Am. 1998;82:909-929.
    2.Portenoy RK. Neuropathic Pain. In: Portenoy RK, Kanner RM, eds. Pain Management: Theory and Practice. Philadelphia, Pa: FA Davis Company; 1996:108-113.
    3.Katz N. Neuropathic pain in cancer and AIDS. Clin J Pain. 2000;16:S41-S48.
    4.Galer BS, Dworkin RH. A Clinical Guide to Neuropathic Pain. Minneapolis, Minn: McGraw-Hill Companies Inc; 2000:100.
  • Cacoub p hcv meh 2014

    1. 1. Extrahepatic Manifestations of Hepatitis C Virus Infection Pr Patrice CACOUB Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie Centre National de Référence Maladies Auto-immunes Hôpital La Pitié-Salpêtrière, Paris, FRANCE
    2. 2. 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
    3. 3. Hepatitis C Virus Chronic Infection: More Than One Target Cell Hepatocyte Choo. Science 1989 • Hepatitis • Cirrhosis • Hepatocarcinoma Lymphocyte Zignego. J Hepatol 1992 Ferri. Blood 1993 • Cryoglobulinemia • Auto-Ab • B-NHL
    4. 4. Cryoglobulinémies mixtes Infection VHC +++ Saadoun, Arch Intern Med, 2006
    5. 5. VASCULARITES: CLASSIFICATION Chapel Hill, révisé en 2012
    6. 6. Les cryoglobulines sont des Immunoglobulines qui précipitent à une température < 37°C et se dissolvent lors du réchauffement Ferri C et al. Orphanet J Rare Dis 2008 Brouet J et al. Am J Med 1974
    7. 7. Cryoprecipitation Endothelial cells 7
    8. 8. Pathogenesis of cryoglobulinaemic vasculitis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 8
    9. 9. Skin Purpura Neuropathy Cryoglobulinemia Vasculitis Membrano-proliferative Glomerulonephritis CNS Vasculitis 9
    10. 10. Mixed Cryoglobulin and Neuropathy Distal Polyneuropathy 80% • Chronic progressive course, • Distal, symetric, axonal PN, mainly sensory • Few extra neurological signs : purpura • Severe liver involvement • Moderate inflammatory syndrome Mononeuropathy Multiplex 20% Cacoub P et al, AIDS 2005
    11. 11. Cryoglobulinemic Membrano-Proliferative Glomerulonephritis GNMP de type 1 Doubles Contours Pseudo-thrombi IgG/IgM Kappa/ lambda C3 ±C1q
    12. 12. HCV Mixed Cryoglobulinemia and Digestive Tract Mesenteric artery stenosis Intestinal wall thickening Terrier B et al, GUT 2011 13
    13. 13. Cardiac Involvement in Hepatitis C Virus-Related Vasculitis Terrier B et al, Am J Cardiol 2013 14
    14. 14. Central Nervous System Involvement in HCV-Cryoglobulinemia Vasculitis  HCV-vasculitis HCV Controls (n=40) (n=11) (n=36) ------------------------------------------------------------------------------------Gender (F/M) 23/17 6/5 20/16 Age (yrs) 59 ± 13 56 ± 10 58 ± 12 WMHS 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<0.01 WMHS: White Matter Hypersignals Casato MPeriventricular Hypersignals PVHS: et al, J Hepatol 2004
    15. 15. Features of Mixed Cr yoglobulinemia Age at disease onset Female/Male ratio Purpura Weakness Arthralgias Arthritis (non-erosive) Raynaud's phenomenon Sicca syndrome Peripheral neuropathy Renal involvement B-cell non-Hodgkin's lymphoma Hepatocellular carcinoma n=250 54 ± 13 (29-72) 3 98% 98% 91% 8% 32% 51% 81% 31% 11% 3% Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009 16
    16. 16. Mixed Cryoglobulin and Distal Polyneuropathy Peripheral Nerve Biopsy - important peri-vascular infiltrate of lymphocyte - around small vessels i.e. venules, capillaries - no PMN, no destruction of the vascular wall
    17. 17. Cellular Infiltrate in HCV-Vasculitis Who’s the culprit ? HCV Core Protein in Skin Vascular Structures 18
    18. 18. Detection of Genomic Viral RNA in Ner ve 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 19
    19. 19. A Role for B Cell Immunity in HCV-Vasculitis Rationale for Rituximab treatment in cryoglobulinemic vasculitis Roccatello, D. et al. Nephrol. Dial. Transplant. 2004 Rocatello D, Nephrol Dial Transplant, 2004 20
    20. 20. J Immunol, 2011
    21. 21. Expansion des Lympho B CD21-/low CD27+ IgM+ chez les patients VHC-MC
    22. 22. Biais de répertoire des Lympho B CD21-/low CD27+ IgM+ avec expression préférentielle de la chaîne lourde d’Ig VH1-69 Accumulation de mutations somatiques témoignant de la maturation d’affinité Terrier B. et al. J Immunol 2011
    23. 23. 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
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