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

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

• 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

Cryoglobulinémies mixtes

Saadoun, Arch Intern Med, 2006

Infection VHC +++

VASCULARITES: CLASSIFICATIONVASCULARITES: CLASSIFICATION

Chapel Hill, révisé en 2012

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

7

Endothelial cells

Cryoprecipitation

8

Pathogenesis of

cryoglobulinae

mic vasculitis

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

9

Skin Purpura

Membrano-proliferative Glomerulonephritis CNS Vasculitis

Neuropathy

Cryoglobulinemia Vasculitis

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%

Cryoglobulinemic Membrano-Proliferative Glomerulonephritis

Doubles Contours

Pseudo-thrombi

GNMP de type 1

IgG/IgM

Kappa/lambda

C3 ±C1q

13

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

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

- 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

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

Terrier B. et al. J Immunol 2011

Accumulation de mutations somatiques témoignant de la maturation d’affinité

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