Extrahepatic Manifestations
of Hepatitis C Virus Infection
Service de Médecine Interne, et CNRS UMR 7087 Université Pierre et Marie Curie
Centre National de Référence Maladies Autoimmunes
Hôpital La Pitié-Salpêtrière, Paris, FRANCE
Pr. Patrice CACOUB
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
3
• Hepatitis • Cirrhosis• Hepatocarcinoma
• Cryoglobulinemia• Auto-Ab• B-NHL
HepatocyteChoo. Science 1989
LymphocyteZignego. J Hepatol 1992Ferri. Blood 1993
Hepatitis C Virus Chronic Infection:
Two Main Target Cells
Cryoglobulinémies mixtes
Saadoun, Arch Intern Med, 2006
Infection VHC +++
5
Endothelial cells
Cryoprecipitation
6
Pathogenesis of
cryoglobulinae
mic vasculitis
Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
7
Skin Purpura
Membrano-proliferative Glomerulonephritis CNS Vasculitis
Neuropathy
Cryoglobulinemia-Systemic Vasculitis
Cutaneous Manifestations of HCV
10
HCV Mixed Cryoglobulinemia & Digestive Tract
Mesenteric artery stenosis
Intestinal wall thickening
Terrier B et al, GUT 2011
Distal Polyneuropathy 80%
Cacoub P et al, AIDS 2005
Mixed Cryoglobulin and Neuropathy
• Chronic progressive course,
• Distal, symetric, axonal PN, mainly
sensory and painful
• Few extra neurological signs :
purpura
• Severe liver involvement
• Moderate inflammatory syndrome
- 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
Cryoglobulinemic Membrano-Proliferative Glomerulonephritis
Doubles Contours Pseudo-thrombi
GNMP de type 1
• Proteinuria (g/d)
• Albumin (g/L)
• Creatinine (mol/L)
• Cryoglobulin (II/III)
• Cryoglobulin level (g/L)
• ALT (IU x N/ml)
• Genotype 1/ 2/ 3/ 4
• Treatment of nephrotic sd plasmapheresis steroids furosemide ACE
3.1 ± 2.2
29 ± 5
118 ± 4116 / 2
1.4 ± 1.8
1.5 ± 1
11/ 3/ 2/ 2
132 (66%)8 (44%)
18 (100%)12 (66%)
HCV & glomerulonephritis
Alric L. Am J K Dis, 2004
IgG/IgM ± IgA
Kappa/lambda
C3 ± C1q
GNMP et VHC: ImmunofluorescenceDépôts immuns endomembraneux (pariéto-mésangiaux)
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
18
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%
Main Features of Mixed Cryoglobulinemia
Ferri C, Mascia MT, Saadoun D, Cacoub P. 2009N = 250
19
HCV Core Protein in Skin Vascular Structures
Who’s the culprit ?
Cellular Infiltrate in HCV-Vasculitis
20
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
21
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
22
A Major Role for T Cell Immunity in HCV-Vasculitis
Abnormal T lymphocytes distribution
Predominant T lymphocytes infiltration in vasculitis lesions
Th1 cytokines profile in vasculitis lesions
MHC-II polymorphism (DR11)
Deficit in Treg lymphocytes
23
Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Vasculitis
Boyer O, Saadoun D et al, Blood 2004
24
Before treatmentOn treatmentEarly F/u Late F/U3
4
5
6
CD
25
hig
h (
% o
f C
D4
+)
44
5
6
Before treat.
On Treat.
Early F/U
Late F/U.
**†
**†
-CR
-NR/PR
0
10
20
30
40
CD25h
igh
(ce
lls/μl)
†*
BeforeTreat.
CR NR/PRAfter Treat.
C
After Treat.
A
Complete clinical response of HCV-vasculitis to anti-viral treatment is associated with an increase in CD4+CD25high Treg cells
Landau DA et al, Arthritis Rheum 2008
25
0 20 40 60 80 1000.0
0.2
0.4
CD25high (cells /μl)C
4 (
g/l
)
R²-0.16, p<0.005
0 20 40 60 80 1000
1
2
3
CD25high (cells /μl)
Cry
og
lob
uli
ns
(g
/l)
R²-0.1, p<0.005
Correlation between Immune Response and Treg Lymphocytes in HCV MC Vasculitis
Landau DA et al, Arthritis Rheum 2008
HCV Cryoglobulinemic Vasculitis Treatments
27
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
Steroids
28
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
HCV eradication
Immunosuppressors
Chemotherapy
Plasma exchange
29
HCV Treatment Efficacy in HCV-Vasculitis%
im
pro
vem
en
t
Zuckerman, J Rheumatol 2000. Naarendorp, J Rheumatol 2001. Cacoub, Arthritis Rheum 2002, Zaja F, Blood 2003. Sansonno D, Blood 2003 , Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007
30
* Clinical remission and SVR
31
Predictive Factors of Response to HCV Therapy in Cryoglobulinemic Vasculitis
Multivariate Analysis
Odds ratio [95%CI] p
• Renal involvement 0.27 [0.08-0.87] 0.02
• Renal insufficiency (GFR<70) 0.18 [0.05-0.67] 0.01
• Daily proteinuria > 1g 0.32 [0.09-1.11] 0.05
• Early virological response 3.53 [1.18-10.59] 0.02
Cacoub, Arthritis Rheum 2005, Saadoun, Arthritis Rheum 2007
32
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immunosuppressors
Chemotherapy
33
Years
Overa
ll su
rviv
all
Overall Survival of 151 HCV-Vasculitis Patients
Terrier B et al. Arthritis Rheum 2010
32 deaths after a median follow-up of 54 months (IQR 26-89)
Causes of death:- Infection (n=10)- Cirrhosis (n=10; 4 HCC)- Non-HCC neoplasia (n=4)- Cardiovascular (n=4)- Renal failure (n=2)- Vasculitis (n=2)- Unknown (n=2)
34
Baseline Prognostic Factors of HCV-Vasculitis Patients
Use of Peg-IFN/riba had a positive prognostic impact
HR = 0.34 (0.16-0.67)
Prognostic Factors
During follow-up
After adjustment on vasculitis severity, immunosuppressants showed a negative
impact
HR = 4.05 (1.75-9.36)
Terrier B et al. Arthritis Rheum 2010
36
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immuno-modulatorsRituximab
37
Rationale for Rituximab treatment in cryoglobulinemic vasculitis
Rocatello D, Nephrol Dial Transplant, 2004Roccatello, D. et al. Nephrol. Dial. Transplant. 2004
38
Treatment of Mixed Cryoglobulinemia Resistant
to Interferon with Rituximab
Sansonno D et al, Zaja F et al, Blood 2003
39
10
20
30
40
50
60
70
80
90
MONTHS
100
6 12
15 (93.7)
13 (81.2)
12 (75)
1 2 3 4 5 7 8 9 1011 24 36 48
10 (62.5)
6 (37.5)
Cryoglobulinemia Vasculitis: Poor Response Maintenance after Discontinuation of
Rituximab
Sansonno D et al, 2007
40De Vita S, Arthritis Rheum 2012
RTX
non-RTX
Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis
41De Vita S, Arthritis Rheum 2012
Rituximab for the Treatment of Severe Cryoglobulinemic Vasculitis
42
HCV Vasculitis: a Two-Faces Disease…Needs a Two Faces Treatment Strategy
Rituximab
PegIFN plus Ribavirin
43
44
Outcome of HCV-MC according to treatment
Parameters All PegIFN-ribavirin RTX-PegIFN-
ribavirinn=93 n=55 n=38 P
Time clinical response, months
6.8 ± 4.7
8.4 ± 4.75.4 ± 4.0
0.004
Clinical response
CR68
(73.1) 40 (72.7) 28 (73.7) 0.98PR 22 (23.6) 13 (23.6) 9 (23.7)NR 3 (3.2) 2 (3.6) 1 (2.6)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Immunological response
CR49
(52.7) 24 (43.6) 26 (68.4) 0.001PR 35 (37.6) 25 (45.4) 10 (26.3)NR 8 (8.6) 6 (10.9) 2 (5.2)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Virological response
SVR55
(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
45
Outcome of HCV-MC according to treatment
Parameters All PegIFN-ribavirin RTX-PegIFN-
ribavirinn=93 n=55 n=38 P
Time clinical response, months
6.8 ± 4.7
8.4 ± 4.75.4 ± 4.0
0.004
Clinical response
CR68
(73.1) 40 (72.7) 28 (73.7) 0.98PR 22 (23.6) 13 (23.6) 9 (23.7)NR 3 (3.2) 2 (3.6) 1 (2.6)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Immunological response
CR49
(52.7) 24 (43.6) 26 (68.4) 0.001PR 35 (37.6) 25 (45.4) 10 (26.3)NR 8 (8.6) 6 (10.9) 2 (5.2)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Virological response
SVR55
(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
46
Outcome of HCV-MC according to treatment
Parameters All PegIFN-ribavirin RTX-PegIFN-
ribavirinn=93 n=55 n=38 P
Time clinical response, months
6.8 ± 4.7
8.4 ± 4.75.4 ± 4.0
0.004
Clinical response
CR68
(73.1) 40 (72.7) 28 (73.7) 0.98PR 22 (23.6) 13 (23.6) 9 (23.7)NR 3 (3.2) 2 (3.6) 1 (2.6)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Immunological response
CR49
(52.7) 24 (43.6) 26 (68.4) 0.001PR 35 (37.6) 25 (45.4) 10 (26.3)NR 8 (8.6) 6 (10.9) 2 (5.2)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Virological response
SVR55
(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
47
Outcome of HCV-MC according to treatment
Parameters All PegIFN-ribavirin RTX-PegIFN-
ribavirinn=93 n=55 n=38 P
Time clinical response, months
6.8 ± 4.7
8.4 ± 4.75.4 ± 4.0
0.004
Clinical response
CR68
(73.1) 40 (72.7) 28 (73.7) 0.98PR 22 (23.6) 13 (23.6) 9 (23.7)NR 3 (3.2) 2 (3.6) 1 (2.6)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Immunological response
CR49
(52.7) 24 (43.6) 26 (68.4) 0.001PR 35 (37.6) 25 (45.4) 10 (26.3)NR 8 (8.6) 6 (10.9) 2 (5.2)Relapse 17 (18.3) 10 (18.1) 7 (18.4)
Virological response
SVR55
(59.1) 33 (60) 22 (57.9) 0.94Death 5 (5.4) 2 (3.6) 3 (7.9) 0.70
48
Course of kidney parameters in HCV-MC according to the type of treatment
PegIFN-ribavirin RTX-PegIFN-
ribavirinn=10 p n=21 p
Kidney inv. CR 4 (40) 17 (80.9) 0.04Creatininemia (µmol/l)Baseline 150 ± 30 217 ± 47EOF 169 ± 44 0.28 136 ± 27 0.03GFR (ml/min)Baseline 58 ± 7 42 ± 5EOF 59 ± 9 0.41 57 ± 4 0.01Daily Proteinuria (gr/d)Baseline 3.1 ± 0.9 3 ± 1EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001
49
Course of kidney parameters in HCV-MC according to the type of treatment
PegIFN-ribavirin RTX-PegIFN-
ribavirinn=10 p n=21 p
Kidney inv. CR 4 (40) 17 (80.9) 0.04Creatininemia (µmol/l)Baseline 150 ± 30 217 ± 47EOF 169 ± 44 0.28 136 ± 27 0.03GFR (ml/min)Baseline 58 ± 7 42 ± 5EOF 59 ± 9 0.41 57 ± 4 0.01Daily Proteinuria (gr/d)Baseline 3.1 ± 0.9 3 ± 1EOF 1.2 ± 0.5 0.046 0.4 ± 0.1 <0.001Hematuria (n,%)Baseline 10 (100) 19 (90.5)EOF 2 (20) 2 (10.5) <0.001
50Dammacco F et al, Blood 2010
RTX/Peg-IFNα-Ribavirin vs. Peg-IFNα-Ribavirin in HCV Systemic VasculitisMaintenance of Complete Response
51
52
Time Course of HCV Viral Load
Terrier B et al. Arthritis Rheum 2009
• If failure or CI of PegINF/riba: RTX alone• Place to be defined for PegIFN/Riba/Previr
54
Chronic HCV infection
Poly- oligoclonal B-cell expansion
AutoantibodiesRF - ICMixed cryoglobulins
Cryoglobulinemic vasculitis
Monoclonal B-cellproliferationOvert lymphoma
Immuno-modulatorsLow dose IL2
55
Reversible Quantitative Deficit in Treg Lymphocytes (CD4+CD25+) in HCV-Systemic
Vasculitis
Before treatmentOn treatmentEarly F/u Late F/U3
4
5
6
CD
25
hig
h (
% o
f C
D4
+)
44
5
6
Before treat.
On Treat.
Early F/U
Late F/U.
**†
**†
-CR
-NR/PR
After Treat.
A
0 20 40 60 80 1000
1
2
3
CD25high (cells /μl)
Cry
og
lob
uli
ns
(g
/l)
R²-0.1, p<0.005
0 20 40 60 80 1000.0
0.2
0.4
CD25high (cells /μl)
C4
(g/l )
R²-0.16, p<0.005
Boyer, Blood 2004. Landau Arthritis Rheum 2008
56
57
Effects of Low-Dose Interleukin-2 on Levels of CD4-Treg in Patients with HCV-Vasculitis, According to Treatment Course (C).
Saadoun D et al, NEJM 2012
Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2 Baseline C1 C2 C3 C4 Post IL-2
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
Baseline C1 C2 C3 C4 Post IL-20
10
20
30
PurpuraNeuropathy
ArthralgiaFatigueKidney Involvement
CD
4+Tr
eg
(%
)C
LIN
ICA
LR
ES
PO
NS
ETemporal Effects of Low-Dose Interleukin-2 on
Clinical Features & Levels of Regulatory T Cells for Each Study Patient
Saadoun D et al, NEJM 2012
59
Effects of Low-Dose Interleukin-2 on Levels on the Ratio of Treg Cells to the sum of Effector T Cells CD4 + CD8 in Patients with HCV-Vasculitis
Saadoun D et al, NEJM 2012
60Saadoun D et al, NEJM 2012
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
% of patients
n = 1614
% of controls
n = 412
Fatigue without depression
Fatigue with depression
Depression without fatigue
No fatigue and no depression
Total
48
5
2
45
100
0.7
0
0
99.3
100
Fatigue without EM
Fatigue with EM
EM without fatigue
No fatigue and no EM
Total
19
35
21
25
100
0.5
0.2
3.4
96
100
Association between fatigue, depression and clinical extrahepatic manifestations (EM)
Poynard T et al. J Viral Hep, 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Multivariate analysisMultivariate analysis
Fatigue (moderate or severe) in comparison to absence of fatigue was associated with:
• female gender,
• age > 50 years,
• cirrhosis or many septa,
• purpura. Independently of these associations, fatigue (moderate-severe)
was associated with : arthralgia, myalgia, paresthesia, sicca sd & pruritus.
Poynard T et al. J Viral Hep, 2002Poynard T et al. J Viral Hep, 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Prevalence of fatigue at baseline and at 18 months follow-up in treated
and untreated patients
Baseline 18 months 18 months vsbaseline
Non treated (n=72) No fatigue Moderate Severe
39 %35 %26 %
42 %39 %19 %
P = 0.74
Sustained responders(n=82) No fatigue Moderate Severe
41 %37 %22 %
69 %24 %7 %
P < 0.001
Relapsers (n= 47) No fatigue Moderate Severe
45 %43 %13 %
40 %45 %15 %
P = 0.68
Non responders (n= 224) No fatigue Moderate Severe
40 %42 %18 %
46 %40 %14 %
P = 0.18
Poynard T et al. J Viral Hep, 2002
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-
35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
0%5%
10%
15%20%25%30%
35%40%
Sustained responders (n = 83)
Impact of Treatment on Extra hepatic Manifestations in HCVpatients.
At Baseline and 18 months Follow-up in Responders.
Cacoub P et al. J Hepatol 2002
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
0%5%
10%15%20%25%30%35%40%
Sustained responders (n = 83) Non responders - RNA + (n = 348)
Cacoub P et al. J Hepatol 2002
Impact of Treatment on Extra hepatic Manifestations in HCVpatients.
At Baseline and 18 months Follow-up in Responders.
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
Auto-antibody production in chronic HCV infection.
0
10
20
30
40
50
60
70
%
A-nuclearA-phospholipidA-thyroglobulinA-smooth muscle≥ one auto-Ab≥ three auto-Ab
Pawlotsky JM, Hepatology 1994. Pawlotsky JM, Ann Intern Med 1994.Prieto J, Hepatology 1996. Cacoub P, J Rheumatol 1997. Cacoub P, Medicine 2000.
Extrahepatic manifestations associated with HCV infection.(Prospective study in 321 HCV patients)
Autoantibody Number %
----------------------------------------------------- Antinuclear 124 41
• A-nucleosome 6 2
• A-DNA 8 3
• A-histone 9 3
• A-ENA 10 3
Cacoub P et al. Medicine 2000; 79: 47-56
Manifestation Prevalence
certainly associated with HCV %-------------------------------------------------------• Vasculitis (PAN, cryoglobulinemia) 5-40 • Fatigue 35-54• Arthralgia-myalgia 25-35• Sicca syndrome 10-25• Autoantibodies 10-40• Thrombocytopenia 20-40• Lymphoma ?
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
B-cell-Non Hodgin’s LymphomaB-cell-Non Hodgin’s Lymphoma
Hepatitis C virusHepatitis C virus
2462 tested2462 tested
13.5 % positive • vs 0-5 % in controlsvs 0-5 % in controls
• vs 5 % in other malignant vs 5 % in other malignant hemopathyhemopathy
469 tested469 tested
0 - 39 %
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007Effects of alpha-interferon on HCV+/SLVL course
After 6 months of IFN alpha treatment in SLVL/HCV+: Complete clinical hematologic response (spleen size < 12 cm,
lymphocytosis <4500/mm3, No cytopenia ):
---> 7/9 HCV RNA negative Partial clinical hematologic response
(spleen size or lymphocytosis decrease >50%) :
---> 2/9 HCV RNA +
Hermine O. et al, N Engl J Med 2002; 347: 89-94
HCV antibodies : B-NHL (< 3%) vs SLVL (15%)HCV antibodies : B-NHL (< 3%) vs SLVL (15%)
----> Splenic lymphoma with villous lymphocytes may be associated with HCV infection
Hepatitis C virus : extrahepatic manifestations, an update 2007Hepatitis C virus : extrahepatic manifestations, an update 2007
Conclusion
Extrahepatic manifestations of HCV infection are
frequent, and may be cured by HCV treatment :
• Systemic vasculitis (cryoglobulinemia, PAN)
• Fatigue
• Arthralgia - myalgia - arthritis (±)
• Auto-antibodies (?)
• Splenic lymphoma with villous lymphocytes
• Thrombocytopenia
76
S. Caillat-Zucman, Paris
P. Ghillani, Paris D. Klatzmann, Paris L. Musset, Paris M. Rosenzwajg, Paris
D. Saadoun, Paris D. Sene, Paris B. Terrier, Paris G. Géri, Paris P. Hausfater, Paris O. Lidove, Paris A. Gatel, St Brieuc J-M. Léger, Paris N. Limal, Paris T. Maisonobe, Paris JC Piette, Paris
Merci
L. Alric, Toulouse M. Bourlière, Marseille P. Halfon, Marseille S. Pol, Paris T. Poynard, Paris V. Thibault, Paris Les membres du GERMIVIC
L. Calabrese, Cleveland M. Casato, Roma C. Ferri, Modena G. Kerr, Washington E. Sasso, Seattle JA. Schifferli, Basel V. Soriano, Madrid