World J Gastroenterol 2007 December 28;13(48): 6518-6528
Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations
and association with cryoglobulinemia in Bulgarian patients
Diana V Stefanova-Petrova, Anelia H Tzvetanska, Elisaveta J Naumova, Anastasia P
Mihailova, Evgenii A Hadjiev, Rumiana P Dikova, Mircho I Vukov, Konstantin G
Tchernev
Abstract
AIM: To assess the prevalence of extrahepatic manifestations in Bulgarian
patients with chronic hepatitis C virus (HCV) infection and identify the
clinical and biological manifestations associated with cryoglobulinemia.
METHODS: The medical records of 136 chronically infected HCV patients were
reviewed to assess the prevalence of extrahepatic manifestations. Association
between cryoglobulin-positivity and other manifestations were identified using
c2 and Fisherâs exact test. Risk factors for the presence of extrahepatic
manifestations were assessed by logistic regression analysis.
RESULTS: Seventy six percent (104/136) of the patients had at least one
extrahepatic manifestation. Clinical manifestations included fatigue (59.6%),
kidney impairment (25.0%), type 2 diabetes (22.8%), paresthesia (19.9%),
arthralgia (18.4%), palpable purpura (17.6%), lymphadenopathy (16.2%), pulmonary
fibrosis (15.4%), thyroid dysfunction (14.7%), Raynaudâs phenomenon (11.8%),
B-cell lymphoma (8.8%), sicca syndrome (6.6%), and lichen planus (5.9%). The
biological manifestations included cryoglobulin production (37.5%),
thrombocytopenia (31.6%), and autoantibodies: anti-nuclear (18.4%), anti-smooth
muscle (16.9%), anti-neutrophil cytoplasm (13.2%) and anti-cardiolipin (8.8%).
All extrahepatic manifestations showed an association with
cryoglobulin-positivity, with the exception of thyroid dysfunction, sicca
syndrome, and lichen planus. Risks factors for the presence of extrahepatic
manifestations (univariate analysis) were: age ⥠60 years, female gender,
virus transmission by blood transfusions, longstanding infection (⥠20 years),
and extensive liver fibrosis. The most significant risks factors (multivariate
analysis) were longstanding infection and extensive liver fibrosis.
CONCLUSION: We observed a high prevalence of extrahepatic manifestations in
patients with chronic HCV infection. Most of these manifestations were
associated with impaired lymphoproliferation and cryoglobulin production.
Longstanding infection and extensive liver fibrosis were significant risk
factors for the presence of extrahepatic manifestations in HCV patients.
INTRODUCTION
Hepatitis C virus (HCV) is associated with a wide spectrum of clinical and
biological extrahepatic manifestations[1-3]. In chronically infected patients,
the virus can trigger an impairment in lymphoproliferation with cryoglobulin
production[3]. Mixed cryoglobulinemia with its complications (skin,
neurological, renal, and rheumatologic) is the most significant extrahepatic
manifestation of HCV infection[4,5]. Mixed cryoglobulinemia can evolve into
B-cell lymphoma in up to 10% of the patien[6,7].
Various non-organ specific auto-antibodies, present in low titers, are noted
during the course of chronic HCV infection[8,9], but they do not influence the
clinical profile of the disease[10]. Chronic HCV infection has been linked to
two skin disorders, porphyria cutanea tarda and lichen planus, particularly with
the involvement of the oral cavity[11,12]. Other possible HCV-associated
diseases are type 2 diabetes mellitus[13], thrombocytopenia[14] and pulmonary
fibrosis[15]. The sicca syndrome, although different from the typical
Sjogrenâs syndrome, also appears to be associated with hepatitis C virus
infection[16,17].
It is unclear whether HCV plays a pathogenic role in the development of thyroid
dysfunction[18]. It is possible, that this extrahepatic manifestation of HCV is
related to treatment with interferon rather than the virus[19].
The most common risk factors associated with extrahepatic manifestations of HCV
infection are older age, female sex, and extensive liver fibrosis[8]. Several
reports from different parts of the world suggest that hepatitis C virus affects
not only the liver, but other tissues, organs and systems as well.
Lymphoproliferative disorders, triggered by the virus, are the most significant
extrahepatic manifestations in South-Eastern Europe, where Bulgaria is located.
The aim of the present study was to determine the prevalence of various
extrahepatic manifestations of chronic HCV infection in our country, to analyze
which extrahepatic manifestations are associated with impaired
lymphoproliferation and cryoglobulin production, and to identify which patients
are at greater risk of developing extrahepatic manifestations.
In our clinical practice, several patients present with extrahepatic
manifestations even in the absence of a clearly defined clinical picture of
hepatic illness. It is important to recognize these manifestations in order to
make an early diagnosis and to initiate therapy in a timely manner.
MATERIALS AND METHODS
Patients
We included 136 Bulgarian patients who were referred to the Department of
Internal Diseases and Gastroenterology of the University Hospital Alexandrovska
during the period from 1996 to 2004. The main reason for patient referral was
elevated liver enzymes. The diagnosis of HCV infection was made by the presence
of anti-HCV antibodies (third generation ELISA) and a positive test for HCV-RNA
(Cobas Amplicor HCV Monitor Test, v. 2.0, Roche Diagnostics). HCV genotypes were
identified by direct sequence analysis (Immunogenetics, Belgium) in 60
patients[20]. HBsAg and HIV positive patients were not included in the study.
Liver biopsy was performed in all patients. The data was collected before the
patients were started on any specific treatment.
Methods
Patient records were reviewed to assess the presence of the following clinical
manifestations: fatigue, arthralgia, Raynaudâs phenomenon, palpable purpura,
paresthesia, renal impairment (proteinuria, creatinine above the upper normal
limit, and hypertension), sicca syndrome (mouth and eyes), thyroid dysfunction
(TSH level below or above the normal range of 0.31-5.00 mU/L), lichen planus
(skin and oral lesions), type 2 diabetes mellitus (hyperglycemia, treated by
hypoglycemic drugs), pulmonary fibrosis (X- ray examination), lymphadenopathy,
and lymphoma. The enlargement of peripheral lymph nodes was detected by
palpation. The enlargement of mediastinal lymph nodes was detected by X-ray
examination, and abdominal lymphadenopathy was detected by abdominal
ultrasonography. Chest X-ray and abdominal ultrasonography were obligatory exams
carried out routinely in all patients admitted to the hospital. Lymph node
enlargement was confirmed by computerized tomography. The diagnosis of lymphoma
was based on morphologic evaluation of lymph node tissue in the patients with
co-existing peripheral lymphadenopathy, and by bone marrow biopsy. Histological
analysis of the enlarged mediastinal and/or abdominal lymph nodes was not
performed because patients refused to provide informed consent for invasive
diagnostic surgical procedures.
Biological data obtained from for each patient included the presence or absence
of cryoglobulins, thrombocytopenia, and auto-antibodies: anti-nuclear (ANA),
anti-smooth muscle (ASMA), anti-neutrophil cytoplasm (ANCA), and
anti-cardiolipin (ACL). The platelet count was obtained from the patientsâ
files. Thrombocytopenia was defined as platelet count ⤠110.109/L.
Cryoglobulins were detected by the Winfield method[21]. Twenty milliliters of
venous blood was obtained from each patient in a pre-warmed (37â) syringe,
allowed to clot at 37â and the serum was separated by centrifugation. The
supernatant was incubated at 4â for 8 d and examined daily for
cryoprecipitate. Indirect immunofluorescence was used for the detection of ANA,
ASMA, and ANCA (IFA/ Binding Site). A positive test for ANA and ASMA was defined
as a titer ⥠1/40, and for ANCA ⥠1/20. Anticardiolipin antibodies (ACL-IgG
and ACL-IgM) were detected by ELISA (Orgentec).
The following demographic and epidemiologic data was collected: age (less or â¥
60 years), sex, the suspected duration of the infection (less or ⥠20 years),
an alcohol intake (less or ⥠50 g/d), and the mode of infection. Questions
regarding the most relevant identifiable HCV risks factors were asked, including
transfusion of blood and blood products, intravenous drug use, surgical
procedures, dental manipulation associated with bleeding, and needle stick
injury in health workers. In patients with a past history of transfusions of
blood and blood products, it was assumed that HCV infection was caused by
contaminated blood and blood products.
The histological abnormalities in liver biopsy specimens, obtained blindly
(Hepafix 1.4 mm, B. Braun, Germany), were scored according to the METAVIR
system[22]. Each liver biopsy sample was assessed for the stage of fibrosis and
grade of histological activity. Liver fibrosis was staged on a scale of 0 - 4,
where 0 = no fibrosis, 1 - portal fibrosis without septa, 2 = few septa, 3 =
numerous septa without cirrhosis, and 4 = cirrhosis. Necroinflammatory activity
was graded on a scale of A0-A3, where A0 = no histological activity, A1 = mild
activity, A2 = moderate activity, and A3 = severe activity.
Statistical analysis
Quantitative data was expressed as mean ± SD. Univariate analysis used the c2-
square or Fisherâs exact test for comparison of qualitative values. An
assessment of the characteristics of HCV infection (demographic, epidemiologic,
histologic), associated with the presence of extrahepatic manifestations, was
performed using univariate and multivariate logistic regression analysis.
Statistical significance was assessed at P < 0.05. Adjusted odds ratio (OR) and
95% confidence intervals (CI) were derived from the coefficient of the final
multivariate logistic model. The analysis was performed with SPSS v.12.0
statistical software.
RESULTS
A total of 136 patients with chronic HCV infection were included in the study,
comprising of sixty-two (45.6%) males and seventy-four (54.4%) females. The mean
age of the patients was 50.16 ± 16.08 years (range 20-80 years). Forty-six
patients (33.8%) were ⥠60 years of age. Thirty-four patients (25.0%) had a
history of alcohol intake (⥠50 g/d).
The suspected duration of infection was ⥠20 years in 70 patients (51.5%) and
< 20 years in 66 patients (48.5%). Genotyping was performed in sixty patients,
fifty-two (87%) had genotype 1, 4 (6.5%) genotype 3, and 4 (6.5%) had mixed
genotypes. Metavir scores for inflammatory activity were: A0 in 5 patients
(3.7%), A1 48 (35.3%), A2 46 (33.8%), and A3 37 patients (27.2%). Metavir scores
for fibrosis were: F0 in 12 patients (8.8%), F1 16 (11.8%), F2 25 (18.4%), F3 27
(19.9%), and F4 in 56 patients (41.1%). Twenty patients (14.7%) were intravenous
drug users. Thirty-seven patients (27.2%) were possibly infected during surgical
procedures. History of dental manipulation with bleeding was detected in 18
patients (13.2%). Needle stick injury was found in 11 health workers (8.1%).
Fifty of the 136 patients (36.8%) had previously been transfused with blood or
blood products. Thirty-eight of these 50 patients were women, who received blood
transfusions during childbirth, and in 33 of these patients the duration of
infection was ⥠20 years. Nineteen of these 38 women were ⥠60 years of age
at the time of presentation. Twenty of these patients had Metavir stage F4, and
10 (10/38) were Metavir F3.
The overall prevalence of individual extrahepatic manifestations is shown in
Table 1. At least one extrahepatic manifestation was identified in 104 patients
(76.5%). The clinical manifestations, in descending order of prevalence were:
fatigue (59.6%), kidney impairment (25.0%), type 2 diabetes mellitus (22.8%),
paresthesia (19.9%), arthralgia (18.4%), palpable purpura predominantly of the
lower extremities (17.6%), lymphadenopathy (16.2%), pulmonary fibrosis (15.4%),
thyroid dysfunction (14.7%), Raynaudâs phenomenon (11.8%), B-cell
non-Hodgkinâs lymphoma (8.8%), sicca-syndrome (6.6%), and lichen planus
(5.9%). All patients with sicca-syndrome had xerostomia, but none had
xerophtalmia. Three patients had skin lesions of lichen planus and five had oral
lesions. The biological manifestations, in descending order of prevalence were:
cryoglobulin (37.5%), thrombocytopenia (31.6%), ANA (18.4%), ASMA (16.9%), ANCA
(13.2%), anti-cardiolipin antibodies (8.8%). The ANA, ASMA and ANCA were present
in low titers (⤠1/160). None of the patients in the study had clearly defined
clinical features of autoimmune liver disease.
The relationship between the presence of cryoglobulins and other extrahepatic
manifestations is shown in Table 2.
Cryoglobulin-positivity was related to the following clinical manifestations:
fatigue, purpura, Raynaudâs
phenomenon, kidney impairment, type 2 diabetes mellitus, arthralgia,
paresthesia, pulmonary fibrosis, lymphadenopathy, and B-cell lymphoma.
Cryoglobulin-positivity was also associated with the following biological
manifestations: thrombocytopenia, and positive ANA, ASMA, ANCA, and
anti-cardiolipin autoantibodies. Three female patients (⥠60 years at the time
of the study) with advanced liver fibrosis and history of blood transfusions
during childbirth, first became cryoglobulin positive and subsequently developed
lymphadenooathy over two, three, and five years respectively. Histological
analysis of the removed lymph nodes showed low-grade non Hodgkin B-cell
lymphoma. The present study did not show any association between the presence of
cryoglobulins and thyroid dysfunction, sicca syndrome, and lichen planus (Table
2).
The demographic, epidemiological and liver histological features associated with
the extrahepatic manifestations were analyzed by univariate and multivariate
logistic regression analysis. The results are shown in Table 3. Using univariate
logistic regression analysis there was a positive correlation between the
presence of extrahepatic manifestations and female sex, older age (⥠60
years), duration of the infection (⥠20 years), transfusion of blood and blood
products, and extensive liver fibrosis (Metavir F4). Univariate analysis did not
show any correlation between extrahepatic manifestations and the mode of
transmission: intravenous drug use (8.7% vs 34.4% for the patients without
extrahepatic manifestations), surgical procedures (27.9% vs 25.5%), dental
manipulation with bleeding (12.5% vs 15.6%), and needle stick injury in health
workers (7.7% vs 9.4%). Univariate logistic regression analysis did not show an
association between extrahepatic manifestations and high grade of inflammatory
activity in the liver (Metavir A3) and alcohol intake of ⥠50 g/d (Table 3).
Multivariate logistic regression analysis showed that the most significant
association was between extrahepatic manifestations and long duration of
infection and advanced liver fibrosis (Table 3).
DISCUSSION
The present study on 136 patients with chronic HCV infection, showed a high
prevalence of extrahepatic clinical and biological manifestations. At least one
manifestation was present in 76.5% of the patients. These results are similar to
those reported in a large prospective French study, in which 74% of 1614
patients with chronic HCV infection had at least one extrahepatic clinical
symptom[23]. By univariate analysis (Table 3) five risks factors were found to
be related with clinical and biological extrahepatic manifestations in our
patients: female sex, age ⥠60 years, transfusion of blood and blood products,
duration of the infection ⥠20 years, and extensive liver fibrosis. By
multivariate analysis (Table 3) the most significant risks factors were the
longstanding infection and extensive liver fibrosis.
Fatigue was the most frequent non-specific clinical symptom in chronic HCV
infection[2]. About 60% patients in this study considered fatigue as the initial
or worst symptom of their disease (Table 1). In a prospective study of 1614
individuals with chronic HCV infection, fatigue was present in 53% of
patients[24]. It is not known what causes fatigue in chronic HCV infection. The
elevated fatigue score[25] is probably related to an increase in serum leptin
levels which may interact with serotonin neurotransmission[26]. Fatigue can be
considered a part of the clinical picture of HCV-associated cryoglobulinemia,
since this symptom was seen more frequently in cryoglobulin-positive than in
cryoglobulin-negative patients (92.2% vs 40.0%, OR 17.6, 95% CI 5.8-53.4).
Hepatitis C virus escapes immune elimination in chronically infected
patients[5]. In such patients, CD81-mediated activation of B cells triggers
mono-oligoclonal B-lymphocyte expansion and the appearance of various
HCV-related autoimmune disorders, including the syndrome of mixed
cryoglobulinemia[6,27]. A recent meta-analysis showed that 44% patients with
chronic HCV infection had circulating immune complexes with cryoprecipitating
properties[28]. In the present study, cryoglobulins were isolated in 51 of the
136 (37.5%) patients, but we were not able to define the type of cryoglobulin in
all the cases. However, there was considerable evidence to suggest that HCV was
associated with type â¡ mixed cryoglobulinemia, with clinical features of
vasculitis which mainly affects the small sized blood vessels of the skin,
joints, nerves, and kidneys[5,29]. Skin is the most frequently involved target
organ[30]. In previous studies, palpable purpura was observed in 10% to 21%
patients with clinically manifested cryoglobulinemic syndrome[11], and in 7% of
all HCV infected patients[8]. We observed palpable purpura, predominantly over
the lower extremities, in 24 of the 136 patients (17.6%), with much higher
prevalence in cryoglobulin-positive than in cryoglobulin-negative patients
(41.2% vs 3.5%, OR 19.1, 95% CI 5.3-68.8). Symptoms related to Raynaudâs
phenomenon were observed in 16 of the 136 patients (11.8 %), with higher
prevalence in cryoglobulin-positive than in cryoglobulin-negative patients
(25.5% vs 3.5%, OR 9.3, 95% CI 2.5-34.7). Pruritus, Raynaudâs phenomenon, and
palpable purpura of the lower extremities are the main skin manifestations of
chronic HCV infection, which is consistent with the findings of previous
studies[11,31,32]. However, considering the high frequency of cryoglobulins in
HCV patients, severe symptomatic mixed cryoglobulinemia with the clinical
presentation of diffuse vasculitis was rare, seen in only 1% of
cryoglobulin-positive patients[23]. Polyarteritis nodosa-type of clinical
presentation was not observed in the present study.
Previous studies have shown that arthralgia is present in 44.7% patients with
HCV-associated mixed cryoglobulinemia[33] and in 19% of all HCV infected
patients[8]. The clinical picture may mimic rheumatoid arthritis, especially
since rheumatoid factor was present in 71% of cases[34], but there was no joint
destruction, and antibodies to cyclic citrullinated peptides, which are highly
specific for rheumatoid arthritis, were absent[35]. In the present study,
arthralgia was present in 18.4% patients, with higher prevalence in
cryoglobulin-positive than in cryoglobulin-negative patients (33.3% vs 9.9%, OR
4.8, 95% CI 1.8-12.2). None of the patients in the present study met the
diagnostic criteria for rheumatoid arthritis.
Peripheral nervous system involvement is a chara-cteristic feature of the more
severe forms of clinically apparent HCV-cryoglobulinemia[3]. Peripheral
neuropathy, manifested by paresthesia, was noted in 17% of all HCV patients[23]
and in 37% to 80% of the patients with HCV-associated mixed
cryoglobulinemia[36,37]. We observed paresthesia in 19.9% of all HCV infected
patients, with a higher prevalence in cryoglobulin-positive than in
cryoglobulin-negative patients (41.2% vs 7.1%, OR 9.2, 95% CI 3.3-25.0). Sensory
nerves are mainly affected in patients with HCV-associated mixed
cryoglobulinemia[38]. Neuropathological data shows axonal degeneration,
differential fascicular loss of axons, signs of demyelinization, and
small-vessel vasculitis with mononuclear cell infiltrates in the perivascular
areas[38,39].
Chronic HCV infection can trigger the immune complex syndrome of cryoglobulin
deposition and type-1 membranoproliferative glomerulonephritis[40]. Diffuse
membranoproliferative glomerulonephritis is found in 83% of cryoglobulinemic
renal disease[41]. Misiani et al[42] found a high prevalence of HCV antibodies
(66%) and HCV RNA (81%) in the serum of patients with cryoglobulinemic
glomerulonephritis. Only 2% of the controls (patients with noncryoglobulinemic
glomerulopathies) had HCV antibodies[42]. In Japan, the virus was found in 60%
patients with membranoproliferative glomerulonephritis[43]. Clinically obvious
renal disease was present in 20% to 30% of cryoglobulin-positive patients with
HCV infection[7,23,44]. In 55% of these patients, the findings include mild
proteinuria, mild microscopic hematuria and mild renal insuffiency[45,46].
Arterial hypertension is present in 80% patients[45,47]. In the present study,
34 of the 136 HCV patents (25%) had mild proteinuria, hypertension and serum
creatinine levels above the upper limit of normal. These symptoms are related to
HCV-cryoglobulinemia, since their prevalence was higher in cryoglobulin-positive
than in cryoglobulin-negative patients (45.1% vs 12.4%, OR 5.5, 95% CI
2.3-12.7). Renal abnormalities during the course of HCV infection are usually
diagnosed in most patients between the fifth and sixth decades of life, and
occur slightly more frequently in women than men[45,48]. Risk factors for the
development of severe renal failure at follow-up of these patients include age,
serum creatinine level, and proteinuria at the onset of renal disease[41].
Cryoglobulin-related nephropathy has been reported to progress to chronic renal
failure requiring dialysis in 10% patients[44], but the overall survival at 10
years was 80%[41].
Case-control studies show an increase in the prevalence of type 2 diabetes
mellitus (14.5% to 24%) in patients with chronic HCV infection[13,49,50]. These
findings have been confirmed in a representative sample of the general
population in the USA[51]. Reports from diverse geographic regions have shown a
2- to 10- fold increase in the prevalence of diabetes in patients with HCV
infection compared to liver disease controls[51-53]. The highest prevalence (up
to 50%) was noted in patients with HCV-associated liver cirrhosis[54-56]. Our
findings are consistent with these studies. We found type 2 diabetes in 31 of
the 136 HCV patients (22.8%), which is higher than the prevalence (8.0%) in the
general population of our country. Antonelli et al[57] found a higher prevalence
(14.4%) of type 2 diabetes in HCV patients with mixed cryoglobulinemia compared
to HCV-negative age-matched controls (6.9%) and the general population in
northern Italy (2.5%-3.3%). We also found a higher prevalence of type 2 diabetes
in cryoglobulin-positive than in cryoglobulin-negative patients (35.3% vs 15.3%,
OR 3.0, 95% CI 1.3-6.8). Given the biology of HCV, which is both hepatotropic
and lymphotropic, an immune-mediated mechanism may explain the raised prevalence
of type 2 diabetes in HCV-patients with mixed cryoglobulinemia[57]. Recent
studies suggest that insulin resistance mediated by proinflammatory cytokines,
rather than a deficit in insulin secretion, is the primary pathogenic mechanism
involved in the development of type 2 diabetes in HCV infection[58].
Soresi et al[59] detected abdominal lymphadenopathy in 22% patients with HCV
infection and persistently normal transaminases, and in 38% of those with high
alanine aminotransferase values. Multiple logistic regression analysis showed a
significant relationship between abdominal lymphadenopathy and histological
abnormalities of the liver, presence of HCV RNA in the serum and gamma-globulin
levels[59]. Lymphadenopathy in chronic HCV infection indicates a possible
interaction between viral antigens and the immune system[60]. This interaction
may be complicated by autoimmunity, cryoglobulinemia and B cell malignancy[60].
In the present study, lymphadenopathy was seen in 22 of the 136 HCV patients
(16.2%), with a higher prevalence in cryoglobulin-positive than in
cryoglobulin-negative patients (35.3% vs 4.7%, OR 11.0, 95% CI 3.4-35.1).
Epidemiological studies have confirmed a link between HCV infection and B-cell
non Hodgkinâs lymphoma[61-63]. In a recent meta-analysis, the prevalence of
HCV infection in patients with B-cell non Hodgkinâs lymphoma was approximately
15%, which is much higher than the prevalence of HCV in the general
population[64]. Clonal B cell proliferation was observed in patients with a
longer duration of HCV infection, type â¡ cryoglobulin, and
vasculitis[5,65,66]. Over 90% patients who developed non-Hodgkin lymphoma had
type â¡ cryoglobulins[64]. About 10% patients with HCV mixed cryoglobulinemia
evolved into lymphoma[6]. In a series of 231 Italian patients with mixed
cryoglobulinemia, 20 developed B-cell lymphoma after a mean of 8.8 years[7]. The
overall risk of non-Hodgkin lymphoma in patients with cryoglobulinemic syndrome
was 35 times higher than that in the general population[64]. Our findings are in
agreement with the results reported from Italy[67]. In the present study, B-cell
non Hodgkinâs lymphoma was diagnosed in 12 of the 136 HCV patients (8.8%) with
higher prevalence in cryoglobulin-positive than in cryoglobulin-negative
patients (17.6% vs 3.5%, OR 5.8, 95% CI 1.5-22.7). The exact prevalence of HCV
associated lymphoma in our country may be much higher, since patients with
abdominal and/or mediastinal lymphadenopathy (without enlargement of peripheral
lymph nodes) did not provide consent for invasive diagnostic surgical
procedures. The appearance of cryoglobulins, peripheral lymphadenopathy and
low-grade B-cell lymphoma in 3 women during follow-up suggested that benign
lymphoproliferation, triggered by the virus, can evolve into malignant B cell
lymphoma. It is possible that genetic and environmental factors[68] play a role
in the higher prevalence of HCV-associated lymphoma in South-East Europe,
including our country, compared to Northern Europe[69]. Based on the available
evidence it appears that HCV is an important risk factor for B-cell malignancy
in areas with a high prevalence of HCV infection[5], which in our country is
1.3%.
Ueda et al[70] noted a higher prevalence of anti-HCV antibodies in Japanese
patients with idiopathic pulmonary fibrosis compared to the general population.
The prevalence of idiopathic pulmonary fibrosis in anti-HCV positive patients
was 9.4%[71]. HCV patients with mixed cryoglobulinemia have been found to have
asymptomatic interstitial lung fibrosis diagnosed by chest X-ray and
high-resolution computed tomography[15]. Pulmonary fibrosis in HCV-related
cryoglobulinemia is perhaps triggered by local deposition of circulating
HCV-containing immune complexes[72]. In the present study 21 of the 136 HCV
patients (15.4%) showed pulmonary fibrosis on routine X-ray examination; the
frequency of pulmonary fibrosis was higher in cryoglobulin-positive than in the
cryoglobulin-negative patients (25.5% vs 9.4%, OR 3.2, 95% CI 1.2-8.6). These
findings need further confirmation with the use of more sophisticated
radiological techniques.
Serum autoantibodies are commonly seen in patients with chronic HCV infection.
In a study by Lenzi et al[9] the overall prevalence of non-organ specific
autoantibodies was significantly higher in anti-HCV positive patients compared
to healthy subjects, and HBsAg positive controls (25% vs 6% and 7%
respectively). Several studies have evaluated the prevalence of ANA and ASMA,
with figures ranging from 4.4% to 41%[8,10,34] and 7% to 66%
respectively[23,34,73]. In the present study, positive ANA and ASMA tests were
seen in 18.4% and 16.9% patients respectively. The anti-ANA and ASMA antibodies
were found in low titers (⤠1/160), and were detected predominantly in the
cryoglobulin-positive patients (Table 2). However, none of the patients had a
clearly defined clinical picture of autoimmune l