Cryoglobulinemia
Creation date: October 2002
Table 1. Classification of Cryoglobulins
| Classification of Cryoglobulins | Composition of cryoprecipitates |
| Type I cryoglobulinemia | simple or single-component (Ig) cryoglobulinemia |
| Type II mixed cryoglobulinemia | polyclonal IgGs + monoclonal IgM |
| Type III mixed cryoglobulinemia | polyclonal IgGs + polyclonal IgMs |
Type I cryoglobulinemia is composed of only one isotype or subclass
of immunoglobulin. Both type II and type III mixed cryoglobulinemia (MC)
are immune complexes composed of polyclonal IgGs, the autoantigens, and
mono- or polyclonal IgMs, respectively; the IgMs are the corresponding
autoantibodies with rheumatoid factor (RF) activity (3-6).
Type I or monoclonal cryoglobulinemia is almost invariably associated
with a well-known hematological disorder and it is frequently asymptomatic
per
se. Similarly, circulating mixed cryoglobulins are commonly detected
in a great number of infectious or systemic disorders (1-6). On the contrary,
"essential" mixed cryoglobulinemia (MC) represents a distinct disorder
(3-6); it can be classified among systemic vasculitides (3-10). The histopathological
hallmark of MC is a leukocytoclastic vasculitis involving small- and medium-sized
vessels and responsible for multiple organ involvement. A frequent synonym
of the disease is the term "cryoglobulinemic vasculitis" which better focus
on the typical histopathological alterations responsible for MC cutaneous
and visceral organ involvement (3, 10).
Etiology of Mixed Cryoglobulinemia
Since the first description of MC syndrome, chronic hepatitis has been
reported as frequent manifestation appearing during the clinical course
of the disease (3-6). Therefore, a possible role for hepatotropic viruses
in the pathogenesis of the disease has long been suggested (3, 11). A role
for hepatitis B virus (HBV) has been firstly investigated; however, HBV
viremia is rarely recorded, while anti-HBV antibodies largely varied among
different MC patient populations (3). It can be estimated that HBV can
represent a causative factor of MC in less than 5% of individuals. Following
the discovery of hepatitis C virus (HCV) as the major etiologic agent of
non-A-non-B chronic hepatitis (12), a great number of clinico-epidemiological,
histopathological, and virological studies (HCV RNA detection by polymerase
chain reaction -PCR- and/or in situ hybridization -ISH) have been definitely
established the relevant role for HCV in the pathogenesis of MC (3, 8-10,
15-19). The prevalence of serum anti-HCV antibodies and/or HCV RNA in MC
patients ranged from 70% to almost 100% among different patient populations
(3, 20).
Etiopathogenesis of MC and its overlapping with other diseases
Because of the frequent association between MC and HCV, the behavior
of MC is closely linked to the natural history of HCV chronic infection
(3). However, the MC is also the result of concomitant genetic and/or environmental
factors, which remain largely unknown. HCV has been recognized to be both
an hepato- and lymphotropic virus, as suggested by the presence of active
or latent viral replication in the peripheral lymphocytes of patients with
type C hepatitis or MC (21-22). Moreover, Bcl-2 recombination in B-lymphocytes
may be observed in a significant percentage of HCV-infected individuals,
particularly in patients with HCV-related MC (23, 24). The activation of
this anti-apoptotic protoncogene may be responsible for B-lymphocyte expansion
and consequent autoantibody production, including the cryoglobulins. Due
to its biological characteristics HCV may be involved in a wide number
of autoimmune and lymphoproliferative disorders (3, 9, 18, 20, 25-31).
Besides MC syndrome, other important HCV-associated disorders are porphyria
cutanea tarda (PCT), autoimmune hepatitis, membranoproliferative glomerulonephritis,
B-cell lymphomas, and other malignancies (3, 9, 18, 20, 25-31). Thus a
frequent clinico-pathological overlapping may exist between MC and other
HCV-related disorders (3, 25).
Diagnosis criteria / classification
There are no available diagnostic criteria for MC; in 1989 the Italian
Group for the Study of Cryoglobulinaemias has proposed preliminary criteria
for MC classification (32). A revised version of these criteria (Table
2), including clinico-pathological and virological findings, has been recently
proposed (3). Circulating mixed cryoglobulins, low C4, and orthostatic
skin purpura are the hallmarks of the disease; moreover, leukocytoclastic
vasculitis, involving medium- and, more often, small-sized blood vessels
(arterioles, capillaries, and venules) is responsible for MC tissue injury
(3-6, 9-10).
Table 2. Proposed criteria for the classification of mixed cryoglobulinaemia
patients.
| criteria | serological | pathological | clinical |
| major | mixed cryoglobulins
low C4 |
leukocytoclastic vasculitis | purpura |
| minor | rheumatoid factor +
HCV + HBV + |
clonal B-cell infiltrates
(liver and/or bone marrow) |
chronic hepatitis
MPGN peripheral neuropathy skin ulcers |
| definite mixed cryoglobulinemia syndrome:
a) serum mixed cryoglobulins (± low C4) + purpura + leukocytoclastic vasculitis b) serum mixed cryoglobulins (± low C4)+ 2 minor clinical symptoms + 2 minor serological/pathological findings |
| essential or secondary mixed cryoglobulinemia:
absence or presence of well-known disorders (infectious, immunological or neoplastic) |
Cryoglobulinemic vasculitis is secondary to vascular deposition of circulating immune-complexes, mainly cryoglobulins, and complement, with the possible contribution of both hemorhelogical and local factors (3, 33). Due to its clinical and histological features, MC is classified among systemic vasculitides, in the subgroup of small vessel vasculitides, which also includes cutaneous leukocytoclastic vasculitis and Schonlein-Henoch purpura (3, 10).
Differential diagnosis
The so-called "essential" MC was first described by Meltzer et al.
in 1966 (5); originally, this term was referred to autonomous disease when
other well known systemic, infectious or neoplastic disorders have been
ruled out by means of a wide clinico-serological work-up.
Given the striking association between MC and hepatitis C virus (HCV)
infection (>90%), the term "essential" is now referred to a minority of
MC patients (<10%) (3). Moreover, HCV is the triggering factor of a
variety of disorders (3, 9, 18, 20, 25-31). In this scenario MC can represent
a crossroads between some autoimmune disorders (autoimmune hepatitis, sicca
syndrome, glomerulonephritis, thyroiditis, etc.) and malignancies (B-cell
lymphomas, hepatocellular carcinoma) (3, 9, 18, 20, 25-31). Therefore,
a careful patient evaluation is necessary for a correct diagnosis of MC
syndrome. It is not rare in clinical practice to observe in the same patient
a slow progression from mild HCV-associated hepatitis to various extrahepatic
manifestations (arthralgias, sicca syndrome, Raynaud’s phenomenon, rheumatoid
factor positivity, etc.), and ultimately to overt MC syndrome with typical
clinico-serological manifestations. In only a minority of MC patients a
malignancy may develop, generally after a long lasting follow up period
(3, 20, 31, 34-36).
For these reasons a clinical monitoring of MC patients is recommended
for a timely diagnosis of life-threatening MC complications, mainly the
nephropathy, widespread vasculitis, and B-cell lymphoma or other malignancies.
Frequency
The prevalence of MC presents great geographic heterogeneity; the disease
is more common in Southern Europe than in Northern Europe or Northern America
(3-9). The disease is considered to be a relatively rare disorder; however,
as yet there are no adequate epidemiological studies regarding its overall
prevalence. Given its clinical polymorphism, a single manifestation
(skin vasculitis, hepatitis, nephritis, peripheral neuropathy, etc.) is
often the only apparent or clinically predominant feature, so that MC patients
are often referred to different specialties. A correct diagnosis might
thus be delayed or overlooked entirely; consequently, the actual prevalence
of MC is probably underestimated.
For the same reasons, the clinical pattern of the MC syndrome may vary
largely among patients series referred to different tertiary care facilities
(3, 6, 8, 19, 37).
It has been estimated that low levels of circulating mixed cryoglobulins
can be detected in over 50% of HCV-infected individuals, while overt cryoglobulinemic
syndrome develops in about 5% (3, 28-29). Because of the wide diffusion
of HCV infection worldwide, a growing incidence of HCV-related MC can be
expected, especially in underdeveloped countries where HCV in the general
population is quite prevalent (3, 38).
Clinical description
MC syndrome is characterized clinically by a triad -purpura, weakness,
arthralgias- and by a series of pathological conditions, including chronic
hepatitis, membranoproliferative glomerulonephritis (MPGN), peripheral
neuropathy, skin ulcers, diffuse vasculitis, and less frequently by lymphatic
and hepatic malignancies (3-10, 19, 25-27, 30-31, 34-37). The clinical
pattern of cryoglobulinemic vasculitis is comparable in patients with type
II or type III MC (3). The prevalence of MC manifestations reported in
Table 3 regards an Italian patient population referred to a rheumatology-immunology
division; a variable patient recruitment at different specialist centers
together with racial differences among patients series is often responsible
for some contrasting data present in the literature (3-10, 19).
At the initial observation, MC can present with different clinico-serological
patterns, varying from isolated serum mixed cryoglobulins, probably expression
of early stage of the disease, to complete cryoglobulinemic syndrome. This
is a combination of serological findings (mixed cryoglobulins with RF activity
and frequent low C4) and clinico-pathological features (purpura, leukocytoclastic
vasculitis with multiple organ involvement). Moreover, incomplete MC,
i.e. mixed cryoglobulinemia with one or two typical MC features (arthralgias,
peripheral paresthesias, mild hepatitis, RF-seropositivity, low C4, etc.)
is frequently found, mainly in rheumatic outpatient clinic. In these subjects
overt MC syndrome can develop during long-term follow-up. On the other
hand, we may see some patients with typical cryoglobulinemic syndrome,
but without serum cryoglobulins, the hallmark of the disease. This is generally
a transient phenomenon due to the wide variability of cryoprecipitable
immune-complex levels (39). Repeated cryoglobulin determinations are necessary
for a correct diagnosis in these subjects;
Table 3. Demographic, clinico-serological and virological features of 200 MC patients
| Age, mean ± SD years (range)* | 54±12 (29-74) |
| female/male ratio | 3 |
| Disease duration, mean ± SD years (range) | 11±6 (1-36) |
| Purpura | 95% |
| Weakness | 94% |
| Arthralgias | 85% |
| Arthritis (non-erosive) | 9% |
| Raynaud's phenomenon | 35% |
| Sicca syndrome | 35% |
| Peripheral neuropathy | 45% |
| Renal involvement** | 31% |
| Liver involvement | 71% |
| B-cell non-Hodgkin's lymphoma | 8.5% |
| Hepatocellular carcinoma | 2.5 % |
| Cryocrit, mean ± SD % | 3.8±7.4 |
| Type II/type III mixed cryoglobulins | 2/1 |
| C3, mean ± SD mg/dl (normal 60-130) | 86±33 |
| C4, mean ± SD mg/dl (normal 20-55) | 11±14 |
| Antinuclear antibodies | 25% |
| Antimitichondrial antibodies | 11% |
| Anti-smooth muscle antibodies | 22% |
| Anti-extractable nuclear antigen antibodies | 8% |
| Anti-HCV antibodies | 92% |
| HCV RNA | 86% |
| Anti-HBV antibodies | 40% |
| HBsAg | 3% |
Diagnostic methods
The main diagnostic parameter of MC is the presence of serum mixed
(IgG-IgM) cryoglobulins. Unfortunately, there are no universally accepted
methodologies for cryoglobulin measurements; however, simple standardized
indications are often sufficient for testing cryoglobulinemia (3, 9, 38).
Due to their thermal instability, the measurement of cryoglobulin level
in the blood should be performed immediately in the same place where the
blood is sampled. For a correct evaluation of serum cryoglobulins it is
necessary to avoid false-negative results due to Ig cold precipitation
also at room temperature: the first steps (blood sampling, clotting, and
serum separation by centrifugation) should be always carried out at 37°C
and the cryocrit determination and cryoglobulin characterization at 4°C
(after 7 days). Moreover, cryocrit determinations (percentage of packed
cryoglobulins referred to total serum after centrifugation at +4°C)
should be done on blood samples without anticoagulation to avoid false-positive
results due to cryofibrinogen. Without the above relatively simple precautions,
not only will the quantities of cryoglobulins measured be incorrect, but
the test may completely fail to even detect cryoglobulins. While the detection
of serum cryoglobulins is fundamental for the diagnosis of MC, the levels
of serum cryoglobulins usually do not correlate with the severity and prognosis
of the disease (3). Very low levels of cryocrit, often difficult to quantify,
can be associated with severe, active cryoglobulinemic syndrome; on the
contrary, high levels of serum cryoglobulins may characterize an oligo-
or asymptomatic disease course. In these subjects, particularly in the
presence of a cryogel phenomenon, rheological alterations due to blood
hyperviscosity can be observed (33, 38). Finally, a sudden decrease or
disappearance of serum mixed cryoglobulins, sometimes associated with abnormally
high levels of C4, can be the presenting manifestation of complicating
B-cell malignancy (40).
The analysis of cryoprecipitates is generally carried out by means
of immunoelectrophoresis or immunofixation. Using more sensitive methodologies,
i.e. immunoblotting or two-dimensional polyacrylamide gel electrophoresis,
type II MC shows a microheterogeneous composition; in particular, oligoclonal
IgM or a mixture of polyclonal and monoclonal IgM can be detected (3, 37,
41). This particular serological subset, termed type II-III MC, could represent
an intermediate, evolutive state from type III to type II.
Management of cryoglobulinemia
Clinical course, treatment, and prognosis of type I cryoglobulinemia
largely depend on the underlying disorder, varying from benign monoclonal
gammopathy of undetermined significance to malignant B-cell neoplasias.
In some individuals, type I cryoglobulinemia may be responsible for hyperviscosity
syndrome ; in these instances a short plasma exchange course is often able
to resolve this complication (3). On the contrary, both type II and type
III MC are often responsible for a more or less severe clinical syndrome
with multiple organ involvement (Table 3). Due to its complex etiopathogenesis
and clinical polymorphism, the treatment of MC is particularly challenging.
For a correct therapeutic approach we must deal with three important factors;
namely, the HCV infection, the presence of autoimmune disorder, and the
possible neoplastic complications (3). Following the etiopathogenesis process
leading from HCV infection to cryoglobulinemic vasculitis we can treat
the disease at different levels by means of different –etiologic, pathogenesis,
symptomatic- therapies (Table 4). Since HCV represents the triggering factor
of the disease as well as it may exert a chronic stimulus on the immune-system
(3, 9, 10, 16, 21-25, 35-36), an attempt at HCV eradication by alpha-interferon
treatment should be done in all cases of HCV-associated MC (3, 10, 42-46).
However, the beneficial effect observed with this drug is often transient
and not rarely associated with important immune-mediated side-effects such
as peripheral sensory-motor neuropathy, thyroiditis, and rheumatoid-like
polyarthritis (47-49). Probably, in predisposed subjects alpha-interferon,
both antiviral and immunomodulating agent, can trigger or exacerbate some
pre-existing, often subclinical, symptoms. Unfortunately, there are no
available parameters for predicting this harmful complication; thus, alpha-interferon
therapy should be avoided at least in those patients with clinically evident
peripheral neuropathy. On the whole, the usefulness of alpha-interferon
treatment in MC patients is limited by the low rate of responders and frequent
side effects. The association of alpha-interferon and ribavirin might achieve
the eradication of HCV infection in a rather significant number of treated
subjects, as recently demonstrated in patients with type C chronic hepatitis
(50-52). Controlled clinical trials are necessary to evaluate the usefulness
of such combination therapy in HCV-associated MC.
Hopefully, with the rapid growth of molecular biology a vaccine against
HCV might be available in the near future. A vaccine-based therapy (54)
with recombinant HCV proteins in HCV-infected individuals could be able
to prevent the progression of viral infection and possibly to interrupt
the self-perpetuating autoimmune mechanism underlying the MC.
In rare cases of non-HCV-associated MC the immunosuppressive treatment,
mainly cyclophosphamide, is still the first-line intervention. For HCV-associated
MC immunomodulating/immunosuppressive treatments should be considered,
especially in patients who have failed to respond to alpha-interferon.
These treatments include steroids, low-antigen-content (LAC) diet, plasma
exchange, and immunosuppressors (3, 54-57). In particular, both traditional
plasma exchange and double-filtration plasma exchange are able to markedly
reduce the levels of circulating immune-complex, especially the cryoglobulins
(100-101). Oral cyclophosphamide (50-100 mg/day for 2-6 weeks) during the
tapering of aphaeretic sessions can reinforce the beneficial effect of
plasma exchange; moreover, it can prevent the rebound phenomenon that may
be observed after the aphaeresis discontinuation. Plasma exchange is particularly
useful in severe MC complications such as active membranoproliferative
glomerulonephritis (Table 4). LAC-diet is a particular dietetic treatment
that can improve the clearance circulating immune-complexes by restoring
the activity of the reticulo-endothelial system, overloaded by large amounts
of circulating cryoglobulins (54, 57). LAC-diet and/or low dosage
of steroids may be sufficient to improve mild manifestations of the MC
(Table 4). Patients with mild-moderate symptoms, such as palpable
purpura, are particularly sensitive to the smallest variations of
daily steroid dosage (1-2 mg). In clinical practice, MC treatment should
be tailored for the single patient according to the severity of clinical
symptoms. Therefore, patients with severe vasculitic manifestations must
be promptly treated with high doses of steroids and/or plasma exchange
and/or cyclophosphamide, while clinically asymptomatic patients usually
do not need any treatment, even in the presence of high levels of cryocrit.
In all cases a careful clinical monitoring of the disease is mandatory,
with particular attention to neoplastic complications.
Table 4. Treatment of HCV-associated Mixed Cryoglobulinaemia
| State of patient | Proposed treatments | |
| Asymptomatic | none | Attempt at HCV eradication |
| Mild manifestations
purpura, weakness arthralgias, arthritis, peripheral sensory neuropathy |
LAC-diet, low dosage of steroids
other symptomatics |
Attempt at HCV eradication |
| Severe manifestations
nephropathy, skin ulcers, sensory-motor neuropathy, widespread vasculitis, active hepatitis |
steroids, plasma exchange, cyclophosphamide, alpha-interferon + ribavirine | Attempt at HCV eradication |
| Cancer
B-cell NHL, HCC |
chemotherapy, surgery | Attempt at HCV eradication |
Unresolved questions
After the first description of MC syndrome as distinct disorder in
1966 (5), the discovery of the association between HCV and MC in the large
majority of patients (3, 17) represents a decisive contribute for a better
comprehension of the pathogenesis mechanisms responsible for the disease,
and consequently for adequate therapeutic strategy.
However, the following questions remain still to be answered:
1- The exact role of HCV in the pathogenesis of the disease; HCV could
be only the triggering factor of the MC or it could also contribute to
the self-perpetuating mechanism of the disease
2- The role of antiviral treatment that could positively affect the
natural history of the disease
3- The possible role of new/alternative therapies
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Key words
Cryoglobulinemia, mixed cryoglobulinemia, cyoglobulinemic vasculitis,
hepatitis C virus, lymphoma