Hepatitis C Induced Mixed
Cryoglobulinemia
7/28/09
Hepatitis C Virus
• Hepatitis C virus (HCV) chronically infects over
170 million people worldwide
• Leading indication for liver transplantation in the
United States and Europe
• HCV is a positive-strand RNA virus with a 9.6-kb
genome that replicates predominantly in the liver
• HCV frequently causes extrahepatic
manifestations, the most common and severe of
which is mixed cryoglobulinemia (MC)
Mixed Cryoglobulinemia
• Cryoglobulins are immunoglobulin complex that
precipitate in the cold and dissolve on rewarming
• Rheumatoid Factor: Ig capable of binding to IgG
(IgM kappa in HCV MC)
• Type II or mixed cryoglobulinemia: Cryoglobulin
that contains both a polyclonal IgG and a
monoclonal IgM rheumatoid factor directed
against the IgG.
• Since the identification of HCV in 1989, it has
been recognized as the cause of >90% of MC
Mixed Cryoglobulinemia
• Systemic vasculitis affecting small- and medium-sized arteries and
veins.
• Characterized by the deposition of immune complexes containing
rheumatoid factor (RF), IgG, HCV RNA, and complement on
endothelial surfaces
• In HCV MC blood tests show elevated serum RF, positive
cryoglobulins and low complement (particularly C4)
Testing for Cryoglobulins
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Serum preparation must be performed at 37degrees C to prevent premature immune complex
precipitation
Serum is stored at 4 degrees C for 7 days, inspected daily for a precipitate, and spun in a for
calculation of cryocrit
A cryocrit >2% is positive (Cryocrit is % of cryoglobulin in serum)
The cryocrit is then typed using immunofixation
MC Clinical Manifestations
• Initially described in 1966 as a clinical triad of
palpable purpura, arthralgia, and weakness
accompanied by organ involvement (e.g.,
nephropathy and neuropathy) and elevated
serum RF
• Now known that this triad is rare, as many MC
patients are asymptomatic
• Primarily affects the small- and medium sized
vessels of the skin, kidneys, and peripheral nerves
Skin Involvement
• Palpable purpura, primarily of the lower legs, occurs in more than 90% of
patients with symptomatic HCV MC
• Frequently intermittent
• Often initial manifestation of HCV MC
• Purpuric lesions may occasionally progress to chronic ulcers and frank
gangrene
Kidney Involvement
• Usually presents as a type I MPGN
• Present in approximately 20 percent of patients
at the time of diagnosis and eventually occurs in
35 to 60% of patients with HCV MC
• New onset HTN can be seen in 80% of cases
• May include hematuria, nephritic to nephrotic
range proteinuria, and variable progression to
chronic renal insufficiency
• Glomerular disease may manifest acutely as
oliguric acute renal failure in 5% of cases
Type 1 MPGN
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Endocapillary mesangial-cell proliferation
Glomerular infiltration by activated macrophages
Glomerular basement membrane shows double contours
Subendothelial deposits of IgM, IgG, and complement components are observed by
immunofluorescence and electron microscopy
Vasculitis of small renal arteries is present in 30% of cases
Eosinophilic PAS-positive intraluminal deposits
Epidemiology of HCV MC
• Estimates of MC prevalence in HCV infection vary
widely, ranging from 10 to 70%
• MC is associated with increased duration of HCV
infection; usually patients with MC have had HCV
infection twice as long as those without MC
• MC may be an independent risk factor for the
development of cirrhosis?
• All HCV genotypes have been found in HCV MC, and
there is no clear association with a particular genotype
• Mixed cryoglobulinemia is more prevalent in Southern
Europe than in Northern Europe and North America
(unclear if this is due to unidentified genetic factors)
HCV Related Lymphoproliferation
Giordona. JAMA 2007. 297 2010-2017
HCV Related Lymphoproliferation
• Likely that HCV MC represents an antigen-driven,
relatively benign clonal B cell lymphoproliferation
• With continued antigenic stimulation, HCV MC
occasionally progresses toward overt NHL
• Typically, the NHL that arises in HCV MC patients
is low-grade and is characterized by clonal RF B
cells
• Consistent with the hypothesis that continued
antigenic presence is required for ongoing clonal
B cell proliferation, eradication of HCV can lead to
disappearance of the associated low-grade NHL
Pathogenesis of HCV-induced B-cell
Lymphoproliferation
• The mechanisms by which HCV leads to the development of B-cell
lymphoma remain unclear
• HCV MC is characterized by aberrant RF B-cell lymphoproliferation
• Elevated B cell-activating factor has been described in HCV MC; B
cell-activating factor inhibits B-cell apoptosis, and high levels may
allow the survival of autoreactive B cells
• Been proposed that HCV infects B cells, leading to direct malignant
transformation via LDL receptors or CD81; however this is less likely
as B cells do not support HCV replication, there is no DNA
intermediate in HCV replication for insertional oncogenesis
• HCV-associated bcl-2 (proto-oncogene) over-expression in the RF
producing B cells has been convincingly demonstrated
• B cell clones in HCV-associated MC and lymphomas often use the
VH1-69 gene and VkA27 segment which is also used by anti-E2
antibodies elicited by HCV
A.L. Zignego et al. / Autoimmunity Reviews 8 (2008) 107–111
Charles ED. KI June 2009
Treatment
• The most effective treatment for HCV MC is eradication of the
underlying HCV infection
• HCV RNA relapse is associated with recurrence of MC and clinical
symptoms
• The current standard of care for HCV infection is pegylated
interferon-a-2a/2b (pIFN) in combination with ribavirin (RBV), which
results in a sustained virological response rate of 45–50% in
genotypes 1 and 4, and 70–80% in genotypes 2 and 3 in HCV
monoinfected patients
• RBV is contraindicated in individuals with creatinine clearance <50
ml/min and pIFN/RBV is poorly tolerated in ESRD
• For patients unable to tolerate antivirals, or for those with severe
renal disease, or for those who have failed to reach sustained
virological response after antiviral therapy, symptomatic treatment
of vasculitis with plasmapheresis, rituximab, or prednisone should
be considered
Antiviral Therapy – IFN alpha
• Randomized trial of 53 patients with HCV MC got
either INF alpha or conventional treatment; about 60%
of the IFN alpha responded with undetectable HCV VL;
improvement of cutaneous lesions, serum Cre,
cryoglobulin and RF titers (Misiani NEJM 1994)
• All patients that that responded had recurrence of
viremia and cryoglobulinemia once interferon alfa-2a
was discontinued
• Interferon alfa therapy may induce and/or exacerbate
glomerulonephritis in some patients with chronic
hepatitis C virus infection
Antiviral Therapy – Pegylated IFN
• Studies have shown reduced clearance of
pegylated interferon in patients on
hemodialysis; however felt safe to use in eGFR
> 15ml/min
• Side effects in dialysis patients include:
anemia, flu-like syndrome, myalgias, and
fatigue
Antiviral Therapy – Pegylated IFN +
Ribavirin
• Ribavirin improves the rate of sustained virologic
clearance when given in combination with standard or
pegylated interferon alfa
• The use of ribavirin is limited by renal insufficiency.
• Among patients with renal insufficiency, the
accumulation of ribavirin induces a severe hemolytic
anemia and iron overload due to chronic hemolyisis
which can lead to an acceleration in liver fibrosis
progression.
• Ribavirin should be used with caution in patients with
mild renal insufficiency. It is NOT recommended for
patients with estimated glomerular filtration rate less
than 50 mL/min per 1.73 m2.
Rituximab
• Chimeric monoclonal antibody that binds to the pan B cell marker,
CD20
• CD20 antigen, is a transmembrane protein expressed on pre-B
lymphocytes and mature lymphocytes
• Effects B cell destruction through complement-dependent and
antibody-mediated cellular cytotoxicity
• Following a standard course of 375 mg/m2/week4 weeks, B cells
are typically undetectable in the periphery, and take 6–18 months
to recover
• Several small studies have shown that 80–93% of patients with HCV
MC vasculitis respond to rituximab, and the reduction of peripheral
VH1-69 memory B cells persists 12 months after treatment
• Symptoms usually reappear with reconstitution of peripheral B cells
• Its use has been associated with modestly elevated (up to two-fold)
levels of HCV viremia
Treatment
Saadoun. Rheumatology 2007;46:1234–1242
KDIGO Recommendations
• For eGFR >50 mL/min/1.73 m2, pegylated
interferon and ribavirin
• For eGFR 15 to <50 mL/min per 1.73 m2,
monotherapy with pegylated interferon
• For eGFR <15 mL/min per 1.73 m2 (including
patients on hemodialysis); monotherapy with
standard interferon that is dose adjusted for a
glomerular filtration rate less than 15 mL/min per
1.73 m
• Antiviral treatment is recommended for at least
12 months
Additional KDIGO Recommendations
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Among MPGN patients with nephrotic-range proteinuria and/or rapid loss of
kidney function and an acute flare of cryoglobulinemia, one of the following
therapies should be considered:
Plasma exchange (3 liters of plasma thrice weekly for two to three weeks)
Rituximab (375 mg/m2 per week for four weeks);
OR
Cyclophosphamide (2 mg/kg per day for two to four months)
Plus Methylprednisolone pulses (0.5 to 1 g/day for three days).
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Treated with ACEI or ARB to reduce proteinuria and achieve target blood
pressure goals
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Relapses of systemic cryoglobulinemia and membranoproliferative
glomerulonephropathy may be treated with additional doses of rituximab
Saadoun. Rheumatology 2007;46:1234–1242