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Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 516-519
High Prevalence of Serum Cryoglobulins in Multitransfused Hemophilic
Patients With Chronic Hepatitis C
By
E. Santagostino,
M. Colombo,
D. Cultraro,
M. Muça-Perja,
A. Gringeri, and
P.M. Mannucci
From the Angelo Bianchi Bonomi Hemophilia and Thrombosis Center and
the Department of Internal Medicine, IRCCS Maggiore Hospital and
University of Milan, Milan, Italy.
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ABSTRACT |
The prevalence, clinical relevance, and risk factors of serum
cryoglobulins in hemophilic patients with chronic hepatitis C virus
(HCV) infection are unknown. We studied 135 consecutive hemophilic
patients (median age, 31 years; range, 10 to 69 years) with chronic
hepatitis C, exposed to the virus for 10 to 41 years. A total of 67 patients were coinfected with the human immunodeficiency virus (HIV),
and 3 (2%) had signs of cirrhosis. Serum samples were tested for the
presence of cryoglobulins, hepatitis B virus (HBV) markers, including
HBV-DNA by hybridization assay, and antibody to HCV by enzyme
immunoassay (EIA). Serum HCV-RNA was tested by polymerase
chain reaction and typed with a hybridization technique. Samples were
also tested for antitissue antibodies, immunoglobulins, rheumatoid factor, and C3 and C4 proteins
of complement. Forty-two hemophiliacs (31%) circulated
cryoglobulins (median levels, 166 mg/L; range, 66 to 480) predominantly
type III (62%; and 29% type II). None of the patients had clinical
signs or symptoms of systemic vasculitis. Cryoglobulinemic patients had
more often serum HCV-RNA (95% v 80%, P < .05),
rheumatoid factor (20% v 6%, P < .05), higher levels of IgG (2,354 ± 682 mg/dL v 1,928 ± 557 mg/dL,
P < .0005) and IgM (323 ± 226 mg/dL v 244 ± 243 mg/dL, P < .05), and lower levels of serum C4 (19 ± 8 mg/dL v 24 ± 8 mg/dL, P < .05) than patients
without cryoglobulins. The risk of producing cryoglobulins was greater
for 114 patients circulating HCV-RNA than for 21 nonviremic patients (odds ratio [OR] = 4.9, 95% confidence
interval [CI] = 1.1 to 22.0) and for the 31 patients with longer
exposure to HCV (more than 26 years) than for the 24 patients with
shorter (17 years or less) exposure (OR = 4.4 95% CI = 1.1 to
18.0). In conclusion a large number of multitransfused hemophiliacs
with chronic HCV infection circulated serum cryoglobulins but none had
clinical signs or symptoms of vasculitis. The risk of developing cryoglobulins parallels the duration of exposure to HCV.
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INTRODUCTION |
SERUM CRYOGLOBULINS, consisting of
polyclonal IgG and either polyclonal or monoclonal (IgM) rheumatoid
factor (mixed cryoglobulinemia) have been detected in 19% to 54% of
patients with chronic hepatitis C virus (HCV) infection.1-5
In 10% to 42% of the cases cryoglobulins were associated with a
systemic vasculitic disorder with such clinical signs as palpable
purpura, arthropathy, peripheral neuropathy, or Raynaud
phenomenon.2,6 The prevalence, clinical relevance, and risk
factors of serum cryoglobulins in patients with chronic hepatitis C are
not well established. Cross-sectional studies of HCV-infected patients
showed a predominance of serum cryoglobulins in women, older patients,
and patients with long-lasting and severe hepatitis.6-8
Other studies found a correlation between serum cryoglobulins and
infection with HCV genotype 2a/c,9 genotype 1b,10 or any genotype.11 Studying serum
cryoglobulins in hemophilic patients with chronic hepatitis C may be
clinically important because the prevalence and clinical significance
of cryoglobulins in these patients are unknown. Moreover,
multitransfused hemophiliacs offer a unique model to evaluate the
relationship between cryoglobulins and the duration of hepatitis C. The
duration of hepatitis C can be established precisely in these patients,
because they have been exposed to HCV at the time of their first
infusion with non-virus-inactivated clotting factor
concentrates.12-14 Therefore, we chose to study 135 multitransfused hemophilic patients with chronic hepatitis C who were
consecutively recruited in this study during their periodic medical
check-up at the Hemophilia Center (Milan, Italy).
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MATERIALS AND METHODS |
Patients.
From June 1995 to July 1996, we studied 135 consecutive anti-HCV
antibody-positive hemophiliacs (134 men; 123 with hemophilia A and 12 with hemophilia B), who were regularly attending the Angelo Bianchi
Bonomi Hemophilia and Thrombosis Center (Milan, Italy) for their annual
medical check-up. The duration of HCV infection was calculated assuming
that the first infusion with blood, plasma, or non-virus-inactivated
concentrates manufactured from large pools of plasma had transmitted
the virus C.12,13 According to this criterion, 128 hemophiliacs have been infected with HCV for 10 to 41 years (median, 23 years). Their main epidemiological and clinical features are shown in
Table 1. In each patient serum alanine
aminotransferase (ALT) values had been measured every year since 1979 and were classified as persistently normal (<40 U/L), intermittently
elevated, and persistently elevated. HCV genotype distribution was 1a
in 39%, 1b in 35%, 1a plus 1b in 3%, 2b in 4%, 2a/c in 2%, 3 in
10%, 4 in 2%, and not performed in 5%. Sixty-seven hemophiliacs
(50%) had serum antibody to human immunodeficiency virus (anti-HIV)
for 11 to 14 years (median, 13 years); 35 (52%) had signs of disease
progression, with CD4 cell counts less than
200/cmm and/or full-blown acquired
immunodeficiency syndrome. These patients were receiving antiretroviral
therapy. None of the patients had received treatment with interferon or steroids in the previous 12 months.
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Table 1.
Epidemiological and Clinical Features of the 135 Hemophilic Patients With Chronic Hepatitis C According to the
Presence or Absence of Serum Cryoglobulins
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Study profile.
Clinical history and physical examination, liver and kidney function,
and routine chemistry tests were obtained in all patients. Special
attention was given to the search for signs and symptoms of cirrhosis
and for cryoglobulinemic syndrome. Cirrhosis was diagnosed clinically
on the basis of laboratory signs of liver failure, ie, platelet count
less than 150,000/mL, serum albumin less than 3.5 g/L, serum
cholinesterase activity less than 4,500 U/L, endoscopic signs of portal
hypertension (presence of esophageal varices and hypertensive
gastropathy), and/or by abdominal ultrasound (irregular margins
of the liver, dilated portal vein, and splenomegaly). All patients were
also examined for signs and symptoms referable to serum cryoglobulins,
ie, palpable purpura, active or healed skin ulcers, peripheral
neuropathy, Raynaud's phenomenon, sicca syndrome, or renal
complications. Joint pain or damage were not considered among possible
symptoms of cryoglobulinemia because hemophilic arthropathy may
be a confounder.
Serum assays.
Cryoglobulins were precipitated from serum stored for up to 8 days at
4°C (0.1 g/L sodium azide). The precipitates were washed five times
at 4°C with 0.15 mol/L NaCl. A fraction of washed cryoglobulins was
then diluted in 0.1 mol/L NaOH, and concentration was measured by
reading the absorbance at 280 nm. Values less than 50 mg/L were
considered negative. Washed cryoglobulins were tested for Ig
composition by immunoblotting according to Musset et al.15 According to Brouet et al,16 cryoglobulins were classified
as type II (if rheumatoid factor was monoclonal) or type III (if rheumatology factor was polyclonal). Serum antinuclear antibodies, antimitochondrial antibodies, antismooth muscle antibodies, and anti-liver-kidney-microsome antibodies were tested for by indirect immunofluorescence. A titer equal or greater than 1:40 was considered positive. The serum Ig, rheumatoid factor, and C3 and
C4 complement fraction levels were measured by routine
nephelometric assays. The upper limit of the normal levels
of the rheumatoid factor was 60 IU/mL.
Anti-HCV was detected with a third-generation enzyme-linked
immunosorbent assay (ELISA; Ortho Diagnostics System, Raritan, NJ).
HCV-RNA was detected by a polymerase chain reaction (PCR) technique
(Amplicor, Roche Diagnostics, Nutley, NJ). HCV genotypes were
determined by a reverse hybridization assay (LiPA; Innogenetics, Brussels, Belgium).17 Hepatitis B virus (HBV)-related
markers were detected by using commercially available kits (Abbott
Laboratories, North Chicago, IL). HBV-DNA was detected by a capture
hybridization assay (Digene, Beltsville, MD). Anti-HIV-1
was detected by using a commercially available ELISA and confirmed by
Western blot (Abbott Laboratories).
Statistical analysis.
Continuous variables were expressed as mean values and standard
deviations. Discrete variables were expressed as median values and
ranges. Categorical values were expressed as frequency and percent
values. The t-test was used to compare means. Logarithmic transformation was used when distribution was not normal. Logistic regression was used to calculate the risk of cryoglobulinemia in
patients with serum HCV-RNA, HIV coinfection, and different duration of
HCV infection. The periods of HCV infection duration were chosen on the
basis of the distribution quartiles of the cohort (10 to 17, 18 to 21, 22 to 26, and greater than 26 years), and the first quartile was used
as reference. The results were expressed as odds ratio and 95%
confidence intervals (CI).
| |
RESULTS |
Forty-five patients (31%) circulated cryoglobulins, with
concentrations ranging between 66 and 480 mg/L (median, 166 mg/L). Cryoglobulins were type III in 26 patients (62%) and type II in 12 (29%). In 4 patients (9%) cryoglobulins were not typed. Although in
patients with type-II cryoglobulin there was a tendency for less severe
liver disease (as expressed by the prevalence of persistently elevated
ALT), differences were not statistically significant (35% v
50% in type III). Age, severity of hemophilia, pattern of serum ALT,
prevalence of cirrhosis, antitissue antibodies, anti-HCV, HBsAg,
HBV-DNA, anti-HIV, and HIV disease progression were similar in patients
with or without serum cryoglobulins (Table 1 and
2). There were no differences in HCV
genotype distribution between cryoglobulinemic and noncryoglobulinemic
patients (data not shown). Conversely, prevalence of serum HCV-RNA
(95% v 80%, P < .05) and of rheumatoid factor (20%
v 6%, P < .05), mean serum levels of IgG (2,354 ± 682 mg/dL v 1,928 ± 557 mg/dL, P < .0005), and IgM (323 ± 226 mg/dL v 244 ± 243 mg/dL, P < .05) were higher in patients with cryoglobulins than in those
without. Instead, the mean serum levels of C4 were lower in
the cryoglobulinemic patients (19 ± 8 mg/dL v 24 ± 8 mg/dL, P < .05; Table 2). None of the patients had or has had
signs of palpable purpura, healed or active skin ulcers, peripheral
neuropathy, kidney failure, sicca syndrome, or Raynaud phenomenon. In
patients with serum HCV-RNA the risk of developing serum cryoglobulins
was 4.9 (95% CI, 1.1 to 22) times that for nonviremic patients and it
remained significantly higher after adjusting for HIV infection
(Table 3). Compared with patients with 10 to 17 years exposure to HCV, the risk of developing cryoglobulins was
2.4 (95% CI, 0.6 to 10.8) for patients with 18 to 21 years exposure to
HCV, 3.7 (95% CI, 1.0 to 14.4) for those with 22 to 26 years exposure,
and 4.4 (95% CI, 1.1 to 18.0) for those with longer than 26 years
exposure. A similar trend was observed after adjusting for HIV
infection. The odds ratio of developing serum cryoglobulins in
anti-HIV-positive patients was 1.6 (95% CI, 0.8 to 3.2) compared with
anti-HIV-seronegative patients (Table 3). Serum levels of
cryoglobulins and type of cryoglobulin distribution were similar in
anti-HIV-positive and -negative patients (data not shown).
Anti-HIV-positive patients had higher serum levels of IgG (2,406 ± 608 mg/dL v 1,720 ± 435 mg/dL, P < .001) and IgM
(295 ± 208 mg/dL v 243 ± 267 mg/dL, P < .05)
than anti-HIV-seronegative patients.
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Table 2.
Virological and Immunological Features of the 135 Hemophilic Patients With Chronic Hepatitis C According to the
Presence or Absence of Serum Cryoglobulins
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Table 3.
Risk of Developing Cryoglobulins in Relation to Serum
HCV-RNA, Length of Exposure to HCV, and Serum Anti-HIV in
Hemophiliacs
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| |
DISCUSSION |
This is the first study evaluating the prevalence, clinical relevance,
and risk factors of serum cryoglobulins in multitransfused hemophilic
patients with chronic HCV infection. Approximately one third of the
patients circulated serum cryoglobulins, which were predominantly type
III with polyclonal rheumatoid factor. Further confirming the strict
association between HCV replication and appearance of serum
cryoglobulins, serum HCV-RNA was more often detected in patients with
cryoglobulins than in those without (95% v 80%, P < .05). Interestingly, despite the relatively high serum levels of
circulating cryoglobulins, none of the patients had clinical signs or
symptoms of systemic vasculitic disorders.
Three previous studies in nonhemophilic patients with HCV-related
chronic hepatitis or cirrhosis found similar rates (35% to 37%) of
serum cryoglobulins.2-4 Another study reported a 54% rate
in patients with chronic hepatitis C.1 These studies showed a tendency for higher rates to occur in women, older patients, and
those with long-lasting HCV-related infection or cirrhosis. Perhaps the
fact that all except one of our hemophilic patients were men and had a
median age of 31 years, and that only few of them had clinical signs of
cirrhosis, would account for the relatively low rate (31%) of serum
cryoglobulins that we observed. Studies in nonhemophilic patients
suggested an association between serum cryoglobulins and genotype 2a/c
or 1b of HCV.9,10 We could not assess whether any HCV
genotype was pathogenetically relevant as to cryoglobulinemia, because
most of our patients were chronically infected with the coagulation
concentrate-related genotype 1 of HCV.18-20
The low rates of genotype 2a/c could be another factor contributing to the relatively low rates of serum cryoglobulin found in
these patients. Finally, it must be pointed out that this study was not
prospective and was based on the evaluation of one serum sample only.
It is possible that cryoglobulins may have appeared and disappeared
over time in hemophilic patients with hepatitis C.
The most important finding of this study was the positive correlation
existing between duration of hepatitis C and risk of producing serum
cryoglobulins. The existence of such a correlation is difficult to show
in nonhemophilic patients, because most of them have community-acquired
hepatitis in which the starting point of infection is difficult to
assess. Another important finding was the absence of clinical signs of
systemic vasculitis in hemophiliacs with cryoglobulins. These data
contrast with those obtained in nonhemophilic patients, showing signs
and symptoms of vasculitis in 10% to 50% of
patients.2,6,20,21 Perhaps such factors as the young age of
our patients and the male sex, which seem to influence negatively the
production of serum cryoglobulins, are also influencing the risk of
vasculitis. Preliminary data indicate that patients infected with HCV
later in life are at higher risk of cirrhosis and liver cancer than
those infected earlier.22-24 Assuming that this holds true
also for the risk of developing serum cryoglobulin-related sequelae,
hemophiliacs could be at low risk of vasculitis because they were
predominantly infected by HCV early in life at the time of the first
infusion with blood products.
Similar prevalences and amounts of serum cryoglobulins were found in
patients with serum anti-HIV and those without, indicating that there
is no obvious association between HIV infection and cryoglobulins.
However, association studies in HIV-infected hemophilic patients should
be interpreted with caution. HIV/HCV-coinfected hemophiliacs could have
more serious HCV-related sequelae than HIV-uninfected patients, but
this is difficult to show by retrospective studies because of the
shortened survival of patients with serum anti-HIV.25,26
In conclusion, a significant number of hemophilic patients with chronic
hepatitis C circulated cryoglobulins, but they had no clinical sign of
vasculitis. Because the risk of developing serum cryoglobulins seems to
increase with the duration of exposure to HCV, a prospective study is
necessary to establish whether or not in these patients serum
cryoglobulinemia will remain asymptomatic or become a clinically
relevant complication of HCV infection.
| |
FOOTNOTES |
Submitted January 9, 1998;
accepted March 17, 1998.
Address reprint requests to P.M. Mannucci, MD, Via Pace 9, 20122 Milano, Italy.
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" is accordance with 18 U.S.C. section 1734 solely to indicate this fact.
| |
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Abstract
Introduction
Abstract