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Chronic hepatitis C virus infection: Prevalence of extrahepatic manifestations a

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Chronic hepatitis C virus infection: Prevalence of extrahepatic

manifestations and association with cryoglobulinemia in Bulgarian

patients

V Stefanova-Petrova, Anelia H Tzvetanska, veta J Naumova,

Anastasia P Mihailova, Evgenii A Hadjiev, Rumiana P Dikova, Mircho I

Vukov, Konstantin G Tchernev

----------------------------------------------------------------------

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V Stefanova-Petrova, Konstantin G Tchernev, Department of

Internal Diseases and Gastroenterology, University Hospital

androvska, Sofia 1431, Bulgaria

Anelia H Tzvetanska, Viral Laboratory, University Pediatric Hospital,

Sofia 1431, Bulgaria

veta J Naumova, Anastasia P Mihailova, Central Laboratory of

Immunology, University Hospital androvska, Sofia 1431, Bulgaria

Evgenii A Hadjiev, Department of Hematology, University Hospital

androvska, Sofia 1431, Bulgaria

Rumiana P Dikova, Department of Pathology, University Hospital

androvka, Sofia 1431, Bulgaria

Mircho I Vukov, National Centre for Health Information, Sofia 1431,

Bulgaria

Correspondence to: Dr. V Stefanova-Petrova, Depart-ment of

Internal Diseases and Gastroenterology, University Hospital

androvska, 1, Georgi Sofiiski Str, Sofia 1431, Bulgaria.

d.petrova.stefanova@...

Telephone: +359-2-9478670 Fax: +359-2-9230654

Received: August 26, 2007 Revised: September 28, 2007

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 Fisher's 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%), Raynaud's

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 & #8805; 60

years, female gender, virus transmission by blood transfusions,

longstanding infection ( & #8805; 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.

© 2007 WJG. All rights reserved.

Key words: Hepatitis C; Liver cirrhosis; Extrahepatic manifestations

http://dx.doi.org/10.3748/wjg.13.6518

Stefanova-Petrova DV, Tzvetanska AH, Naumova EJ, Mihailova AP,

Hadjiev EA, Dikova RP, Vukov MI, Tchernev KG. Chronic hepatitis C

virus infection: Prevalence of extrahepatic manifestations and

association with cryoglobulinemia in Bulgarian patients. World J

Gastroenterol 2007; 13(48): 6518-6528

http://www.wjgnet.com/1007-9327/13/6518.asp

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

Sjogren's 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 androvska 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, Raynaud's 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 patients' files. Thrombocytopenia was defined as

platelet count & #8804; 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 (37 & #8451;) syringe, allowed to clot at

37 & #8451; and the serum was separated by centrifugation. The supernatant

was incubated at 4 & #8451; 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 & #8805; 1/40, and for ANCA & #8805; 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 & #8805; 60 years), sex, the suspected duration of the infection

(less or & #8805; 20 years), an alcohol intake (less or & #8805; 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 Fisher's 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 & #8805; 60 years of

age. Thirty-four patients (25.0%) had a history of alcohol intake ( & #8805;

50 g/d).

The suspected duration of infection was & #8805; 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 & #8805; 20 years. Nineteen

of these 38 women were & #8805; 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%), Raynaud's phenomenon

(11.8%), B-cell non-Hodgkin's 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 ( & #8804; 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, Raynaud's

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 ( & #8805; 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 ( & #8805; 60 years), duration of

the infection ( & #8805; 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 & #8805; 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 & #8805; 60 years, transfusion of blood and

blood products, duration of the infection & #8805; 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 & #8545; 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 Raynaud's 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, Raynaud's 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 Hodgkin's

lymphoma[61-63]. In a recent meta-analysis, the prevalence of HCV

infection in patients with B-cell non Hodgkin's 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 & #8545;

cryoglobulin, and vasculitis[5,65,66]. Over 90% patients who

developed non-Hodgkin lymphoma had type & #8545; 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

Hodgkin's 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 ( & #8804; 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 liver

disease. Recent data suggests that the HCV core particles

concentrated in the cryoprecipitate play a role in the interaction

between the cryoglobulins, endothelial cells and neutrophil

granulocytes[74]. The main antigens in HCV patients with a positive

ANCA test are proteinase 3 and dihydrolipoamine dehydrogenase[75]. A

positive ANCA has been found in 10% patients with HCV-associated

mixed cryoglobulinemia[76]. In the present study, ANCA was present in

18 of the 136 patients (13.2%), with higher prevalence in

cryoglobulin-positive than cryoglobulin-negative patients (25.5% vs

5.9%, OR 5.4, 95% CI 1.9-16.4). HCV patients with ANCA had a higher

prevalence of skin involvement, anemia, abnormal liver function tests

and elevated alpha feto-protein levels[75]. Anticardiolipin

antibodies have been observed in 3.3% to 22% of HCV patients[77-79].

These antibodies were found more frequently in patients with HCV-

associated cryoglobulinemia[80]. Our findings are consistent with

previously reported data. In the present study, 12 of the 136

patients (8.8%) had anticardiolipin antibodies, 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). According to a

recent study, these antibodies do not have any clinical significance

in HCV patients, since they are anti-b2-glicoprotein & #8544;independent[78].

The auto-antibodies seen in patients with HCV infection appear to

resemble those seen in chronic viral infections - the autoantibody

titers are low, frequently found during the clinical course of

cryoglobulinemia, but do not produce a typical autoimmune disease

[29,80].

The prevalence of thrombocytopenia is higher in patients with chronic

HCV infection than in the general population[14]. In a series of 368

patients with chronic HCV infection, Nagamine et al[81] detected 151

cases (41%) of thrombocytopenia. Our findings also suggest a high

prevalence of thrombocytopenia in patients with chronic HCV infection

(31.6%). This can be explained by the large number of patients with

cirrhosis in the present study. Platelet sequestration and

destruction in the spleen[82,83], along with low thrombopoetin

production[83,84] play an important role in the pathogenesis of

thrombocytopenia. However, a direct viral infection of the

megakariocytes[85] and autoimmune mechanisms[86,87] cannot be ruled

out. The higher prevalence of thrombocytopenia in cryoglobulin-

positive than in cryoglobulin-negative patients (58.8% vs 15.3%, OR

7.9, 95% CI 3.5-17.8) in the present study may reflect the role of

immune dysregulation in causing both abnormalities.

In previous studies, thyroid specific antibodies were observed in

22.1% patients with chronic HCV infection, but the presence of

thyroid dysfunction was not different compared to age and gender

matched controls[18]. Thyroid dysfunction was seen in 14.7% of our

136 untreated HCV patients, and there was no association with the

presence of cryoglobulins. However, up to 12.6% HCV patients

developed thyroid dysfunction during or after IFN therapy[88-90],

with a significant association with female gender[91].

Lymphocytic infiltration of the salivary glands has been described in

57% patients with chronic HCV infection compared to 5% in deceased

controls[16]. A direct role of the virus is suggested by studies on

mice expressing HCV envelope proteins E1 and E2 in the liver and

salivary glands[92]. Sialadenitis developed in 84% HCV infected mice

compared to 2% in control littermates and 0% in HCV core transgenic

animals[92]. Up to 10% patients with chronic HCV infection may

develop symptoms of xerostomia and xerophthalmia[8], whereas less

than 5% of patients with confirmed Sjogren syndrome are carriers of

HCV[17]. In the present study, xerostomia was seen in 6.6% patients,

but none had xerophthalmia. Our results show a much higher prevalence

of xerostomia in cryoglobulin-positive patients, however there was no

difference compared to those without cryoglobulins (Table 2). In a

French study, the classic Sjogren syndrome (xerostomia,

xerophthalmia, histological stages & #8546; and & #8547; in the Chilshom scale,

and

anti-SSA or anti-SSB antibodies) was observed only in 1% of patients

with chronic HCV infection[32].

Clinical studies, predominantly from the Mediterranean area and

Japan, suggest that lichen planus, mainly the oral form, is

associated with HCV infection[93-95]. The overall prevalence of anti-

HCV antibodies in Spanish patients with lichen planus was 29.2%[12].

Nagao et al[93] found serum anti-HCV antibodies in 28 (62%) and serum

HCV RNA in 27 (60%) of 45 Japanese patients with oral lichen planus.

However, these results have not been confirmed by reports from other

regions[32,96]. The geographical differences could be related to

immunogenetic factors since the allele HLA-DR6 is expressed in a

significant proportion of Italian patients with oral lichen planus

and HCV infection[95]. The frequency of lichen planus in our HCV

patients (5.9%) is similar to that reported by Pawlotsky et al[32] in

France (5%). We found oral lesions of lichen planus in 5 patients and

skin lesions in 3 patients. In the present study, we did not find any

association between cryoglobulinemia and the presence of lichen

planus (Table 2). Pilli et al[97] detected HCV-specific T cells with

phenotypic and functional characteristics of terminally

differentiated effector cells at the site of the oral lesions. These

findings and the detection of HCV RNA strands in the lichen tissue

[98] suggests a possible role for HCV-specific T-cell responses in

the pathogenesis of lichen planus associated with HCV infection[99].

Our study has demonstrated a high prevalence of extrahepatic

manifestations in Bulgarian patients with chronic HCV infection. Most

of these manifestations are the consequence of impaired

lymphoproliferation and show an association with cryoglobulin

production. Clinical features such as fatigue, palpable purpura,

Raynaud's phenomenon, arthralgia, paresthesia, kidney impairment,

type 2 diabetes, pulmonary fibrosis, lymphadenopathy, B cell

lymphoma, thrombocytopenia and non-organ specific autoantibodies can

be regarded as a part of the clinical spectrum of HCV-associated

cryoglobulinemia. On the other hand, thyroid dysfunction, sicca-

syndrome and lichen planus are also seen in patients with chronic HCV

infection, but were not associated with the presence of cryoglobulins

in the present study. Extrahepatic manifestations were observed more

frequently in older women with longstanding infection, advanced liver

fibrosis and HCV infection acquired through transfusion of blood and

blood products during childbirth. These findings suggest that the

dose of the virus and the route of transmission may be important

factors associated with extrahepatic manifestations. The long

duration of HCV infection and extensive liver fibrosis were the most

frequent findings associated with extrahepatic manifestations, but

the pathogenesis of such an association is unclear[1,23]. Progression

of liver fibrosis and the development of systemic-portal venous

anastomosis allows the passage of antigens directly into the systemic

circulation, thus bypassing the liver filter and resulting in chronic

interaction with the immune system[23]. Some of the immunological

defects are the consequence of HCV interaction with dendritic cells

and a shift from Th1 to Th2 cytokine profile[100,101].

Patients with chronic HCV infection have a high prevalence of

extrahepatic manifestations. These manifestations are found more

frequently in the patients with a long duration of infection and

liver cirrhosis, even in the absence of a clearly defined clinical

picture of hepatic illness. Most of these manifestations are

associated with impaired lymphoproliferation and cryoglobulin

production, triggered by hepatitis C virus. The benign

lymphoproliferation, associated with cryoglobulinemia, can evolve

into malignant B cell lymphoma. Physicians should be aware of the

extrahepatic signs and symptoms of HCV infection. HCV should be

tested in all patients with these manifestations. This may lead to

early diagnosis and successful treatment of chronic HCV infection.

COMMENTS

Background

Hepatitis C virus (HCV) affects not only the liver, but other

tissues, organs, and systems as well. In our practice, several

patients with chronic HCV infection present with extrahepatic

manifestations, even in the absence of a clearly defined clinical

picture of hepatic illness. Lymphoproliferative disorders, triggered

by the virus, are frequently seen in South-Eastern Europe, where

Bulgaria is located.

Research frontiers

The aim of the present study was to assess the prevalence of

different extrahepatic manifestations in Bulgarian patients with

chronic HCV infection, to identify extrahepatic manifestations

associated with impaired lymphoproliferation and cryoglobulin

production, and to determine which patients are at greater risk of

developing extrahepatic manifestations of chronic HCV infection.

Innovations and breakthroughs

We observed a high prevalence of extrahepatic manifestations (76.5%)

in patients with chronic HCV infection. Patients with longstanding

infection and cirrhosis had a higher risk of developing such

manifestations. In the present study, most of the extrahepatic

manifestations were associated with impaired lymphoproliferation and

cryoglobulin production, with the exception of sicca syndrome,

thyroid dysfunction and lichen planus. The presence of B-cell non

Hodgkin's lymphoma was observed in 8.8% patients, with a higher

prevalence in cryoglobulin-positive compared with cryoglobulin-

negative patients (17.6% vs 3.5%, OR 5.8, 95% CI 1.5-22.7).

Applications

Physicians should be aware of the extrahepatic signs and symptoms of

HCV infection. HCV should be tested in patients who have any of these

manifestations. This may lead to early diagnosis and successful

treatment of chronic HCV infection. The treatment of

lymphoproliferative disorders, including B-cell non Hodgkin's

lymphoma poses a challenge, and requires new therapeutic strategies.

Terminology

Hepatitis C virus (HCV) escapes immune elimination. HCV interacts

with hepatocytes and B lymphocytes through a common (CD81) receptor.

CD81-mediated activation of B cells in chronically infected patients

can trigger clonal B-lymphocyte proliferation with cryoglobulin'

production, and evolution of disease into B-cell non Hodgkin's

lymphoma. HCV can interact, with or without immune mediated

mechanisms, with different tissues, organs, and systems.

Peer review

The authors assessed the prevalence of extrahepatic manifestations in

Bulgarian patients with chronic HCV infection and identified the

clinical and biological manifestations associated with

cryoglobulinemia.

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