THE CLINICAL SPECTRUM OF LYMPHOPROLIFERATIVE DISORDERS IN
HCV INFECTION: FROM CRYOGLOBULINEMIA VASCULITIS TO NON
Patrice Cacoub, MD
Department of Internal Medicine and CNRS UMR 7087
Hôpital La Pitié-Salpêtrière
Vasculitides can be divided into primary forms, for which the etiology is unknown, and
secondary forms that result from an autoimmune condition or known infection. The interest in
infection-related vasculitides has been boosted for the last two decades by the development of
new molecular techniques and the proof of true associations between viral hepatitis C and
systemic vasculitis. A wide variety of extrahepatic manifestations has been reported to be
associated with HCV infection, the most frequent being mixed cryoglobulins. Viral factors
that avoids immune elimination leads to accumulation of circulating immune complexes, and
autoimmune phenomena associated with chronic HCV infection. Extrahepatic manifestations
may also be favor by the lymphotropism of HCV which is thought to be involved in the
production of autoantibodies and occurence of non-Hodgkin's B-cell lymphoma (B-NHL).
More than 40% of HCV-infected patients have circulating immune complexes with
cryoprecipitating properties, named mixed cryoglobulins (1,2). Circulating mixed
cryoglobulins are frequently detected in HCV infected patients whereas overt
cryoglobulinemia vasculitis develops in only 5-10% of cases. Mixed cryoglobulinemia (MC)
is a systemic vasculitis, that mainly affects the small and, less frequently, medium size vessels
(3,4). MC is characterized by the proliferation of B-cells clones producing pathogenic IgM
with rheumatoid factor (RF) activity. MC led to clinical manifestations ranging from the so
called MC syndrome (purpura, arthralgia, asthenia) to more serious lesions with neurologic
and renal involvement. Shortly after the discovery of HCV in 1989, there has been evidence
that more than 80% of cryoglobulinemia vasculitis were associated with HCV infection. The
primary role of HCV in the mechanism of cryoprecipitation is mainly suggested by its
selective concentration in cryoglobulins (3,4). Molecular evidence of antigen-driven B-cell
proliferation is definitively provided in HCV-associated type II MC, and HCV appears as the
key trigger. MC not related to HCV infection currently represents less than 10% of mixed
cryoglobulinemia. 1) Clinical features of cryoglobulinemia vasculitis
The most frequently target organs are skin, joints, nerves and kidney. The disease expression
is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-
threathening complications (glomerulonephritis, widespread vasculitis). Purpura
Skin is the most frequently involved target organ and is the direct consequence of the small
size vessel vasculitis. The main symptom is palpable purpura which is reported in 70 to 90%
of patients (5,6). Readily preceded by sensations of cutaneous burns, it frequently reveals
HCV-MC disease, occurs preferentially during winter, is non pruriginous and intermittent. It
always begins at the lower limbs and may extend to abdominal area, less frequently to the
trunk and upper limbs. It persists 3 to 10 days with a residual brownish pigmentation. Skin
biopsy shows a non specific leukocytoclastic vasculitis involving small size vessels with an
inflammatory infiltrates and, in some cases, fibrinoid necrosis of the arteriolar walls and
endovascular thrombi. Raynaud's syndrome and acrocyanosis, which may evolve to digital
ulcerations, are found in ∼ 20% of patients. Arthralgia
Arthralgia are reported in 60 to 90% of HCV-infected patients with MC (4-6). They are
bilateral and symmetric, non-deforming and involved mainly great articulations, knees and
hands, more seldom elbows and ankles. Arthritis is rarely reported. There is no joint
destruction. Rheumatoid factor activity is found in 70-80% of MC patients. Antibodies to
cyclic citrullinated peptide, which are highly specific of rheumatoid arthritis, are absent. Nervous system
The prevalence of peripheral nervous system involvement can be as high as 50% of cases (7).
Neurologic manifestations range from pure sensory axonopathy to mononeuritis multiplex.
The most frequent form is a distal sensory or sensory-motor polyneuropathy. Bilateral
asymmetrical polyneuropathies represent approximately 45 to 70 % of the MC-
polyneuropathy and mononeuropathies multiplex 30 to 55 %. In patients with distal
polyneuropathy, nerve conduction studies are in keeping with a predominantly axonal
process, mainly affecting sensory nerves. Neuropathological data show axonal degeneration,
differential fascicular loss of axons, signs of demyelinization and small-vessel vasculitis with
mononuclear cell infiltrates in the perivascular area (8,9).
Reports on well-documented central nervous system involvement in patients with HCV-
associated vasculitis are rare, though it may be the initial extra hepatic manifestation of HCV
infection (10). Stroke episodes, transient ischemic attacks, progressive reversible ischemic
neurological deficits, lacunar infarctions, or encephalopathic syndrome may occur. MRI
findings of the brain are consistent with ischemia, showing either small lesions of the
periventricular white matter and the cerebral trunk, or extensive supra- and infratentorial
white matter lesions. In a recent prospective study, neuropsychological tests and cerebral MRI
in HCV-MC vasculitis patients (11) showed that the number of impaired cognitive functions
and the number of total and peri-ventricular white matter high intensity signals were
significantly higher in MC vasculitis patients compared to HCV controls. Renal involvement
Renal manifestations are reported in 20 to 30 % of MC patients (1,4,6,12). Chronic type-I
membranoproliferative glomerulonephritis with sub-endothelial deposits represents more than
70 to 80% of cryoglobulinemic renal diseases. It is strongly associated with the type II
cryoglobulinemia with IgMκ rheumatoid factor. The most frequent presentation (55%) is
proteinuria with microscopic hematuria and a variable degree of renal insufficiency. Acute
nephrotic (20%) or acute nephritic (25%) syndrome can also reveal cryoglobulinemic renal
involvement. New onset arterial hypertension is seen in 80 % of cases. Early complement
component (C1q, C4) are very low. Chronic uremia develops in 10-20% of MC patients.
Morphological features are characterized by an important monocytes infiltrates with double
contours of the basement membrane, large, eosinophilic and amorphous intra-luminal
thrombi. Immunofluorescence show intra-glomerular sub-endothelial deposits of IgG, IgM
and complement components. Vasculitis of small renal arteries is present in one third of
patients. In less than 20 % of cases, histological damages correspond to mesangioproliferative
or focal proliferative glomerulonephritis.
In asymptomatic HCV infected patients, the significance of cryoglobulins in the development
of cirrhosis has been the subject of speculation. A meta-analysis of 19 studies on a total of
2,323 patients with chronic HCV infection found a 44% prevalence of cryoglobulinemia.
There was a highly significant association between cirrhosis and cryoglobulinemia after
adjustement for age, gender and duration of infection (13). In a recent personal study of 437
consecutive HCV infected patients, we found advanced liver fibrosis and steatosis in 37% and
35% of MC patients, respectively. In multivariate analysis, MC increased by nearly 3 fold the
risk to have advanced liver fibrosis and steatosis. There was no significant difference in
degree of liver lesions between symptomatic and asymptomatic patients with cryoglobulins. Sicca syndrome
A sicca syndrome is reported in 20 to 40% of MC patients, although a definite Sjögren
syndrome is rarer. Sjögren's syndrome can be distinguished from this condition based on
several differences, including absence of anti-SSA and anti-SSB antibodies, pericapillary (and
non pericanalary) lymphocytic infiltrate, and lack of glandular canal damages. There is no
improvement of the sicca syndrome under anti-HCV therapy (14). Other manifestations
Patients may present with digestive bleeding due to a mesenteric vasculitis, a dyspnea due to
interstitial lung fibrosis, pleural effusions, or intra-alveolar haemorrhages, and a cardiac
involvement with by mitral valvular damages, coronary vasculitis, myocardial infraction,
pericarditis or congestive cardiac failure. Special focus on polyarteritis nodosa (PAN) related to HCV
The prevalence of anti-HCV Ab in patients with a medium size vessel vasculitis of PAN type
has been reported from 5 to 12 % (15). In a prospective study of 1,614 HCV-infected patients,
the PAN-type of presentation was noted in 1% (10). Differentiation between PAN type and
MC vasculitis can be difficult since both diseases may share same clinical manifestations and
pathologic lesions including peripheral neuropathy, purpuric skin lesions, arthralgia, myalgia,
renal involvement, and vascular inflammatory infiltrate. Patients with HCV PAN present
however with different features than those with MC vasculitis, i.e. life-threatening systemic
vasculitis, severe multifocal sensorimotor neuropathies, cerebral angiitis, ischemic abdominal
pain, kidney and liver microaneurysms, increased erythrocyte sedimentation rate and C-
reactive protein level, and renal insufficiency (15). Neuromuscular biopsies typically show
necrotizing vasculitis lesions involving medium size arteries with mononuclear and
polymorphonuclear neutrophil cell infiltrates. 2) Biological features of cryoglobulinemia vasculitis.
Precautions are necessary to avoid false negative results of cryoglobulin determination as a
result of Ig cold precipitation. The first steps (blood sampling, clotting, and serum separation
by centrifugation) should always be carried out at 37°C, and the cryocrit determination and
cryoglobulin characterisation done at 4°C (after seven days). Immunofixation or Western-blot
allows the quantification of Ig in the cryoprecipitate and sometimes may identify oligoclonal
cryoglobulins (16). A threshold of cryoglobulin level higher than 50 mg/liter is usually
considered to be significant.
Serum cryoglobulin values usually do not correlate with the
severity and prognosis of the disease, although higher serum cryoglobulin level was
evidenced in symptomatic patients (17).
Other biological abnormalities may indirectly appreciate MC activity (low CH50 and C4
complement level) or suggest its presence (rheumatoid factor, monoclonal Ig.). Low C2 and
C4 levels is an important finding in cryoglobulinemia vasculitis to distinguish this vasculitis
from (normo- or hypercomplementemic) ANCA-associated vasculitides. A rheumatoid factor
activity is frequently observed, in up to 70% of patients but anti-cyclic citrulinated peptide Ab
are rarely found (<5%). Other immunological abnormalities in HCV infected patients include
the presence of antinuclear (17-41%), anti-cardiolipin (20-27%), anti-smooth muscle cell (9-
40%) and anti-thyroglobulin antibodies (8-13%) (1,2,4,5).
3) Natural history of cryoglobulinemia vasculitis
Some circumstances predispose HCV infected patients to develop mixed cryoglobulinemia
vasculitis such as female gender, advanced age, alcohol consumption above 50 gr/day, longer
duration of infection, type II MC, higher MC serum levels, clonal B cell expansions in both
the blood and liver, HCV genotype 2 or 3, and extensive liver fibrosis (5, 18,19). The worse
pronostic factors are an age older than 60 years at diagnosis and renal involvement. The
overall 5 years survival after the diagnosis of vasculitis range from 90% to 50% in case of
renal involvement. In a recent retrospective Italian study of 231 patients, 79 of 97 deaths were
linked to vasculitis (46% of whom one third due to renal involvement), cancer or hemopathy
(23%), and liver disease (13%) (19).
HCV MC increases the risk of B-NHL. MC reflects the expansion of B-cells producing a
pathogenic IgM with rheumatoid factor activity. Because cryoglobulin producing B-cells in
HCV infected patients are mostly monoclonal, HCV associated MC can be viewed as a
benign B-cell lymphoproliferative condition. Clonal B cell expansion has been demonstrated
in liver, blood and bone marrow of patients with chronic HCV infection in the absence of
overt B cell malignancy. Clonal B cell proliferation are likely observed in patients with longer
duration of HCV infection, type II cryoglobulins, and particularly those with vasculitis (18).
The B cell repertoire in mixed cryoglobulinemia is highly restricted (20,21). Epidemiological
studies have suggested a link between HCV and B-cell non Hodgkin's lymphoma (NHL) (22-
24). In a recent meta-analysis, the prevalence of HCV infection in patients with B-cell NHL
was approximately 15%, much higher than the seroprevalence of HCV in the general
population (25). Although most histological subtypes of B-cell lymphomas have been
described in association with HCV, lymphoplasmocytic lymphoma, diffuse large cell
lymphoma and marginal zone lymphoma are more prevalent in HCV infected individuals 4) Pathogenesis of HCV cryoglobulinemia vasculitis: involvement of cellular immunity
Mixed cryoglobulinemia represent an example of immune complex vasculitis. The antigens
that promote cryoglobulinemia vasculitis remained unknown for a long time until numerous
evidences proved the major role of HCV. Several pathological characteristics make its
specificity: nature of the vessels involved (small size vessels, i.e. arteries, capillaries,
veinules), nature of the inflammatory infiltrate (lymphomonocytic rather than
polymorphonuclear), site of inflammation (mainly perivascular with few wall infiltrates)
(7,8,9,15). The pathogenesis of HCV-MC vasculitis is complex and is likely to involve many
mechanisms. Neutrophilic infiltration with leukocytoclastic changes, typical of immune
complex-mediated vasculitis has seldom been found, while the presence of lympho-histiocytic
infiltrates suggest a T cell-mediated pathogenesis, and only a minor role for the humoral
The mechanisms of in-vitro cryoprecipitation remain unclear. The solubility of proteins
depends on various factors, such as concentration, temperature, pH, and ionic strength of the
solutions, as well as the surface charge. Changes in the primary structure of the variable
portion of Ig, a reduced concentration of sialic acid and reduced amount of galactose in the Fc
portion of the Ig may also explain the different solubility of the cryoglobulins.
There is some evidence of an important role of vascular cell adhesion molecule-1 (VCAM-1),
a molecule exclusively involved in mononuclear cell recruitment, in the pathogenesis of
severe forms of HCV-MC vasculitis (26). Patients with HCV-MC vasculitis often have a
disturbed peripheral blood T cell repertoire, with a high frequency of T cell expansions.
CD4+CD25+ regulatory T cells, which have been shown to control autoimmunity, are
significantly reduced in HCV-MC vasculitis patients (27). Further evidence that T cells help
in the production of cryoglobulins is the influence of HLA type II polymorphism on the
production of HCV-related cryoglobulins (28). In a transgenic mouse model expressing a
human IgM RF, the CD40L-CD40 interaction was required for promoting the survival of RF
precursors and stimulating RF synthesis. Inflammatory infiltrates of lymphocytes and
monocytes around small and pre-capillary arterioles are a feature of MC vasculitis
neuropathy. Monocytes and memory/activated T-lymphocytes accounted for the bulk of
leukocytic cells, while B-cells are more rarely found. Both CD4 and CD8-positive T cells
accumulate in vasculitic nerves lesions (29). The increased expression of interferon (IFN)-γ
and tumor necrosis factor-α in the vasculitic nerves, associated with the absence of typical
type 2 cytokines (interleukin (IL)-4, IL-5 and IL-13), points to a strong polarized type 1
immune response. The up-regulation of macrophage inflammatory protein (MIP)-1α, MIP-1β
and IFN-γ inducible protein 10 (CXCL10) and its specific receptor CXCR3, which all
influence type 1 T cell differentiation, is also consistent with these findings (29). This is
in agreement with previous data obtained from peripheral blood mononuclear cells and
liver (30). 5) Therapy for cryoglobulinemia vasculitis
Before HCV era, cryoglobulinemia vasculitis was treated like other vasculitides. Most of the
data are derived from small uncontrolled studies. In severe systemic disease, patients were
treated with high-dose corticosteroids, cyclophosphamide and plasmapheresis. The outcome
of these patients was considered to be very unfavorable, with a high mortality rate. The
antiproliferative action of interferon (IFN)-α was thought to be effective in cryoglobulinemia
vasculitis. After HCV era, anti-HCV therapy, corticosteroids, immunosuppressive agents, and
plasmapheresis have been proposed as treatments, but the optimal therapeutic regimen
remains controversial. The treatment of HCV-associated MC with severe organ involvement
may target either the HCV viral trigger or the downstream pathogenic events by means of less
specific approaches such as corticosteroids, immunosuppressors or plasmapheresis.
Treatment of HCV-related cryoglobulinemic vasculitis with standard IFN-α is associated with
a relatively poor response and a high relapse rate, especially in severe cases (31). Clinical
improvement of HCV-related vasculitis correlated with virological response, i.e. negative or
significant decrease in serum HCV RNA level. Combination therapy with IFN-α and ribavirin
demonstrated enhanced efficacy on main HCV-related vasculitic manifestations (cutaneous,
100% ; renal, 50% ; and neural, 25-75%). In the largest published study (32) patients with
HCV systemic vasculitis received IFN-α during 20 ± 14 months, associated with ribavirin for
14 ± 12 months. After a mean follow-up of 57 months, 25/27 patients (93%) were alive and
followed as outpatients, whereas 2 patients died secondary to cirrhosis. Most patients (75%)
with a negative viremia at the end of follow up were complete clinical responders for their
vasculitis. Two studies reported a loss of proteinuria and hematuria in sustained viral
responders treated by IFNα plus ribavirin (33,34). In a recent pilot study (32), Peg-IFNα plus
ribavirin achieved a higher rate of complete clinical response in a shorter treatment period (14
months) than those previously reported with IFNα and ribavirin.
A combination of corticosteroids and immunosuppressants such as cyclophosphamide and
azathioprine has been used for the control of severe vasculitis (membranoproliferative
glomerulonephritis, severe neuropathy and lifethreatening complication) while awaiting the
generally slow response to antiviral treatments. In a large retrospective study of 105 patients
with renal disease associated with cryoglobulinemia vasculitis, 80% were administered
corticosteroids and/or cytotoxic agents, while 67% underwent plasmapheresis (34). Despite
this aggressive approach, long lasting remission of the renal disease was achieved in only
14% of cases, and the 10-year survival rate was 49%.
Corticosteroids, used alone or in addition to IFN-α, did not improve the response of HCV-
related vasculitic manifestations in controlled studies. Low dose corticosteroids (prednisone <
10 mg/d) may help to control minor intermittent inflammatory signs such arthralgia, but do
not succeed in cases of major organ involvement (i.e. neurologic, renal), or in the long-term
control of vasculitis.
Plasmapheresis offers the theoretical advantage of removing the pathogenic cryoglobulins
from the circulation of patients with HCV- MC vasculitis. Immunosuppressive therapy is
usually needed in order to avoid the rebound in cryoglobulin level after discontinuation of
apheresis. When used in combination with anti-HCV treatment, plasmapheresis did not
modify the virologic response if IFN-α was given after each session.
More recently, some Italian groups have reported on the efficacy of anti-CD20 monoclonal
antibody (Rituximab) in patients with HCV-MC vasculitis resistant or intolerant to IFN-α
monotherapy (35,36). Rituximab proved effective on skin vasculitis manifestations, subjective
symptoms of peripheral neuropathy, arthralgia and low grade B-cell lymphoma. However,
one potential concern regarding the use of such therapy is its propensity to worsen HCV
viremia (35), which may lead patients to develop more severe HCV-induced liver lesions
and/or cryoglobulinemic relapses (37,38). These studies did not allow conclusions to be
drawn concerning the efficacy of anti-CD20 monoclonal antibody on peripheral neuropathy
and nephropathy. The absence of efficacy on HCV viral clearance and the potential increase
in HCV viral load stresses the need for combined antiviral therapy to block the HCV infection
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Practice Parameters for the Evaluationand Management of Constipation Charles A. Ternent, M.D., Amir L. Bastawrous, M.D., Nancy A. Morin, M.D.,C. Neal Ellis, M.D., Neil H. Hyman, M.D., W. Donald Buie, M.D., and The StandardsPractice Task Force of The American Society of Colon and Rectal Surgeons T he American Society of Colon and Rectal methods of care or exclusive of methods of care
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