Cryoglobulinemia Research Articles

Extrahepatic immune related manifestations in chronic hepatitis C virus infection.

The association of chronic hepatitis C with immune related syndromes has been frequently reported. There is a great range of clinical manifestations affecting various systems and organs such as the skin, the kidneys, the central and peripheral nervous system, the musculoskeletal system and the endocrine glands. Despite the high prevalence of immune related syndromes in patients with chronic hepatitis C, the exact pathogenesis is not always clear. They have been often associated with mixed cryoglobulinemia, a common finding in chronic hepatitis C, cross reaction with viral antigens, or the direct effect of virus on the affected tissues. The aim of this review is to analyze the reported hepatitis C virus immune mediated syndromes, their prevalence and clinical manifestations and to discuss the most supported theories regarding their pathogenesis.

CXCR3 and CXCL10 in autoimmune thyroiditis

The chemokine (C-X-C motif) ligand 10 (CXCL10, also called IP-10) was initially identified as a chemokine that is induced by interferon (IFN)-γ. CXCL10 exerts its function through binding to chemokine (C-X-C motif) receptor 3 (CXCR3). CXCL10 and its receptor, CXCR3, appear to contribute to the pathogenesis of many autoimmune diseases, organ specific (such as type 1 diabetes, Graves' disease and ophthalmopathy), or systemic (such as systemic lupus erythematosus, mixed cryoglobulinemia, Sjogren syndrome, or systemic sclerosis). The secretion of CXCL10 by CD4+, CD8+, and natural killer is dependent on IFN-γ. Under the influence of IFN-γ, CXCL10 is secreted by thyrocytes. Determination of high level of CXCL10 in peripheral fluids is therefore a marker of a T helper 1 orientated immune response. High levels of circulating CXCL10, have been shown in patients with autoimmune thyroiditis (AT). Among patients with AT, CXCL10 levels were significantly higher in those with a hypoechoic ultrasonographic pattern, that is a sign of a more severe lympho-monocytic infiltration, and in those with hypothyroidism. For these reasons it has been postulated that CXCL10 could be a marker of a stronger and more aggressive inflammatory response in the thyroid, subsequently leading to thyroid destruction and hypothyroidism. Further studies are needed to investigate whether CXCL10 is a novel therapeutic target in AT.

Autoimmune and neoplastic thyroid diseases associated with hepatitis C chronic infection.

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographic signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender versus healthy controls, or hepatitis B virus infected patients. In patients with “HCV-associated mixed cryoglobulinemia” (MC + HCV), a higher prevalence of thyroid autoimmune disorders was shown not only compared to controls, but also versus HCV patients without cryoglobulinemia. Patients with MC + HCV or HCV chronic infection show a higher prevalence of papillary thyroid cancer than controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC + HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine, but normal levels of Th2 (C-C motif) ligand 2 chemokine, than patients without thyroiditis. HCV thyroid infection could act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete interferon-γ and tumor necrosis factor-α. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function, particularly where nodules occur, is recommended in HCV patients.

Thyroid involvement in hepatitis C - associated mixed cryoglobulinemia.

The prevalence and clinical features of thyroid involvement in patients with hepatitis C virus-associated mixed cryoglobulinemia (MC+HCV) have been reviewed. A PubMed Medline search was conducted through December 2011 to identify all studies that reported thyroid involvement in MC+HCV patients. Reference lists of the papers initially detected were manually searched to identify additional relevant reports. Studies had to contain sufficient and clear information to be included. In MC+HCV patients, the following thyroid autoimmune abnormalities were significantly more frequent than in controls: high levels of serum anti-thyroperoxidase autoantibody (AbTPO); high levels of serum AbTPO and/or anti-thyroglobulin autoantibody; humoral and ultrasonographical signs of thyroid autoimmunity (35% vs 16%); prevalence of subclinical hypothyroidism (11% vs 2%). Also, the prevalence of papillary thyroid cancer has been found higher in MC+HCV patients than in controls, in particular in patients with autoimmune thyroiditis. The involvement of T helper 1 immunity and chemokine (C-X-C motif) ligand 10 (CXCL10) may be the pathogenetic basis of the association between MC+HCV and thyroid autoimmunity. These results show a high prevalence of thyroid disorders in patients with MC+HCV and point to the need for careful monitoring of thyroid function in these patients.

Cryoglobulinemia and the α-chemokine IP-10

IFN-γ-induced protein 10 (IP-10) and its receptor, CXCR3 chemokine (C-X-C motif) receptor 3 (CXCR3), appear to contribute to the pathogenesis of HCV related mixed cryoglobulinemia (HCV+MC). The secretion of IP-10 by CD4+, CD8+ and natural killer (NK)-T cells is dependent on interferon (IFN)-γ, which is itself mediated by the interleukin (IL)-12 cytokine family. Under the influence of IFN-γ, IP-10 is secreted by several cell types including lymphocytes, hepatocytes, endothelial cells, fibroblasts, etc. In tissues, recruited T helper (Th) 1 lymphocytes may be responsible for enhanced IFN-γ and tumor necrosis factor (TNF)-α production, which in turn stimulates IP-10 secretion from the cells, therefore creating an amplification feedback loop, and perpetuating the autoimmune process. High levels circulation of IP-10 have been found in HCV+MC, especially in patients with clinically active vasculitis. Furthermore, HCV+MC patients with autoimmune thyroiditis (AT), have higher levels than those without AT. Further studies are needed to investigate interactions between chemokines and cytokines in the pathogenesis, and to evaluate whether IP-10 is a novel therapeutic target in HCV+MC.

A review on thyroid autoimmune disorders and HCV chronic infection

Frequently, patients with hepatitis C virus (HCV) chronic infection have high levels of serum anti-thyroperoxidase and/or anti-thyroglobulin autoantibodies, ultrasonographical signs of chronic autoimmune thyroiditis, and subclinical hypothyroidism, in female gender, vs healthy controls, or hepatitis B virus infected patients. In patients with "HCV-associated mixed cryoglobulinemia" (MC+HCV), a higher prevalence of autoimmune thyroid disorders was shown not only compared to controls, but also compared to HCV patients without cryoglobulinemia. Patients with MC+HCV or with HCV chronic infection, show an higher prevalence of papillary thyroid cancer than in controls, in particular in patients with autoimmune thyroiditis. Patients with HCV chronic infection, or with MC+HCV, in presence of autoimmune thyroiditis, show higher serum levels of T-helper (Th)1 (C-X-C motif) ligand 10 (CXCL10) chemokine than patients without thyroiditis. Probably, HCV thyroid infection acts by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes, that secrete interferon-gamma and tumor necrosis factor-alpha. These cytokines might induce a further CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, that may lead into the appearance of autoimmune thyroid disorders in genetically predisposed subjects. A careful monitoring of thyroid function and nodules are recommanded in HCV patients.

Hepatitis C virus associated glomerulopathies.

Hepatitis C virus (HCV) infection is a systemic disorder which is often associated with a number of extrahepatic manifestations including glomerulopathies. Patients with HCV infection were found to have a higher risk of end-stage renal disease. HCV positivity has also been linked to lower graft and patient survivals after kidney transplantation. Various histological types of renal diseases are reported in association with HCV infection including membranoproliferative glomerulonephritis (MPGN), membranous nephropathy, focal segmental glomerulosclerosis, fibrillary glomerulonephritis, immunotactoid glomerulopathy, IgA nephropathy, renal thrombotic microangiopathy, vasculitic renal involvement and interstitial nephritis. The most common type of HCV associated glomerulopathy is type I MPGN associated with type II mixed cryoglobulinemia. Clinically, typical renal manifestations in HCV-infected patients include proteinuria, microscopic hematuria, hypertension, acute nephritis and nephrotic syndrome. Three approaches may be suggested for the treatment of HCV-associated glomerulopathies and cryoglobulinemic renal disease: (1) antiviral therapy to prevent the further direct damage of HCV on kidneys and synthesis of immune-complexes; (2) B-cell depletion therapy to prevent formation of immune-complexes and cryoglobulins; and (3) nonspecific immunosuppressive therapy targeting inflammatory cells to prevent the synthesis of immune-complexes and to treat cryoglobulin associated vasculitis. In patients with moderate proteinuria and stable renal functions, anti-HCV therapy is advised to be started as pegylated interferon-α plus ribavirin. However in patients with nephrotic-range proteinuria and/or progressive kidney injury and other serious extra-renal manifestations, immunosuppressive therapy with cyclophosphamide, rituximab, steroid pulses and plasmapheresis should be administrated.

No evidence of Polyomavirus and EBV infections in Italian patients with mixed cryoglobulinemia infected chronically with HCV

Mixed cryoglobulinemia is a lymphoproliferative disorder associated with hepatitis C virus (HCV). In patients chronically affected by HCV the prevalence of mixed cryoglobulinemia is variable ranging from 0% to 56%. To verify whether polyomaviruses (PyV) play a role in this disorder a total of 222 blood samples from 63 HCV chronic patients, 43 with mixed cryoglobulinemia, 59 chronic lymphocytic leukemia, 50 polytransfused patients, and 50 blood donors were evaluated for Merkel (MCPyV), BKV, JCV, and SV40. EBV was additionally included in the analysis since association with this disorder has been reported. Mixed cryoglobulinemia patients infected chronically with HCV resulted negative for both PyV and EBV. MCPyV was found in 1 subject with Merkel Cell Carcinoma, in 10% of polytransfused and in 10% of blood donors while EBV was detected in 22% of polytransfused, 10% of B-cell lymphatic leukemia patients and 4% of blood donors (P < 0.01). Taken together, the absence of PyV and EBV in HCV-mixed cryoglobulinemia patients seems to exclude a direct involvement of these viruses in the pathogenesis of this disease while the presence of MCPyV in healthy individuals, at the same rate as in polytransfused patients, may reinforce data on a minimal role of this virus in other human pathologies.

Association between HCV induced mixed cryoglobulinemia and pulmonary affection: The role of TNF-alpha in the pathogenesis of pulmonary changes

Background and aim of the workChronic hepatitis C virus (HCV) infection is associated with both pulmonary involvement and cryoglobulinemia. Therefore, this study was designed to investigate the relationship between pulmonary involvement and mixed cryoglobulinemia in chronic HCV infected patients and to investigate the role of TNF-alpha in the pathogenesis of pulmonary changes. Subjects and methodsAfter hospital ethics committee approval and formal patient consent were obtained, 100 patients with compensated hepatitis C virus infection as confirmed by PCR were recruited in this cross sectional study. Their demographic and laboratory data, abdominal ultrasound findings, pulmonary function tests (spirometry), arterial blood gas (ABG) parameters, TNF-alpha levels, and data from high-resolution chest CT were collected and analyzed using SPSS version 16, and a serum cryoglobulin assay was performed in all of the studied patients. ResultsThe prevalence of mixed cryoglobulinemia was 61.7% in the studied HCV patients. Pulmonary symptoms were observed in more than half of these patients. The most common complaint among the symptomatic patients was dyspnea (51.7%), followed by cough (43.3%). Oxygen saturation (Spo2 and Sao2%), and FEV1 and FVC levels, were significantly decreased in the cryoglobulin positive patients compared to the cryoglobulin negative patients. A statistically significant correlation was found between the presence of cryoglobulins and FEV1 level, FVC level, serum albumin level, viremia level, thrombocytopenia and arterial blood gas parameters. No correlation was found between cryoglobulinemia and TNF-alpha level. ConclusionsThe results of this study suggest that pulmonary involvement is common in patients with chronic HCV infection and mixed cryoglobulinemia. Cryoglobulinemia may lead to pulmonary involvement through vascular and interstitial deposition of cryoglobulins, which results in impaired gas exchange and airway affection.

Essential mixed cryoglobulinemia manifesting as recurrent perioral edema: report of a case

Cryoglobulins are immunoglobulins that precipitate in vitro at temperatures <37°C but that redissolve if heated; they are broadly divided into 3 classes. Cryoglobulinemia has a plethora of clinical manifestations, but it typically presents a vasculitic syndrome, most notably a triad of purpura, arthralgia, and weakness secondary to cryoglobulin deposition in small or medium-sized blood vessels. The highly variable clinical presentation and inconsistent laboratory isolation of cryoglobulins mean that the diagnosis may be one of exclusion or of retrospective review. We describe a case of a 67-year-old woman whose principal symptom was recurrent perioral edema, which was characteristically induced by cold. Raised cryoglobulins combined with a positive autoantibody screen suggested mixed cryoglobulinemia secondary to Sjögren syndrome. However, in the subsequent 6 years, she has remained generally well, having developed no autoimmune, neoplastic, or other disease, suggesting the diagnosis is one of "essential" mixed cryoglobulinemia. No treatment other than symptomatic analgesia has been required.

Cutaneous lesions and finger clubbing uncovering hypocomplementemic urticarial vasculitis and hepatitis C with mixed cryoglobulinemia

Urticarial vasculitis is a rare clinicopathologic entity characterized by urticarial lesions that persist for more than 24 hours and histologic features of leukocytoclastic vasculitis. Patients can be divided into normocomplementemic or hypocomplementemic. The authors report the case of a healthy 49-year-old woman with a 1-year history of highly pruritic generalized cutaneous lesions and finger clubbing. Laboratory tests together with histopathologic examination allowed the diagnosis of hypocomplementemic urticarial vasculitis, chronic hepatitis C and type II mixed cryoglobulinemia. The patient started symptomatic treatment and was referred to a gastroenterologist for management of the hepatitis C, with progressive improvement of the skin condition. The development of hypocomplementemic urticarial vasculitis in the context of chronic hepatitis C is exceedingly rare and possible pathogenic mechanisms are discussed.

Scleritis and retinal vasculitis associated with a type II mixed cryoglobulinemia

The patient, a 64-year-old man, with a past history of an IgM monoclonal gammopathy of undetermined significance (MGUS), presented with a 5-day history of ocular pain and redness in his left eye. The best-corrected visual acuity was conserved at 25/25 in both eyes. Topical instillation of phenylephrine did not blanch leading to the diagnosis of temporal anterior non-necrotizing scleritis (Figure 1a). Fluorescein fundus …

Measuring the Response of Extrahepatic Symptoms and Quality of Life to Antiviral Treatment in Patients with Hepatitis C

Background. HCV infection is associated with musculoskeletal manifestations such as chronic widespread pain, sicca syndrome, polyarthritis, and a reduced HRQOL. Little data is available on the effect of treatment on these manifestations. This study measured changes in extrahepatic symptoms and HRQOL before and after antiviral treatment in a large UK patient cohort. Methods. 118 patients completed HQLQ and rheumatological questionnaires before and after treatment with pegylated interferon-α and ribavirin, with specific regard to chronic widespread pain, sicca syndrome, and sustained virological response. Results. There was significant improvement in HQLQ domains of physical functioning, physical disability, social functioning, limitations and health distress due to hepatitis, and general health. There was significant deterioration in domains of positive well-being, health distress, and mental health. There was a significant decline prevalence of CWP (26.3% versus 15.3%, P = 0.015). Sicca syndrome prevalence fell insignificantly (12.7% versus 11%). SVR was associated positively with all HRQOL changes and significantly with CWP remission. Conclusions. HCV antivirals significantly improve poor HRQOL scores and CWP. Before treatment, both were common, coassociated, and unaccounted for through mixed cryoglobulinemia alone. Although a role of the hepatitis C virus in CWP cannot be deduced by these results, symptomatic improvement via antiviral treatment exists for this subset of patients.

Non-ischemic Cardiomyopathy Secondary to Pegylated Interferon in a Patient with Chronic Hepatitis C

Purpose: Reversible cardiomyopathy is a side effect of interferon treatment, typically described as being associated with high-dose standard interferon. Pegylated INF has a polyethylene glycol molecule attached to the protein, which results in a reduction in its rate of absorption, renal clearance, and immunogenicity following subcutaneous injection. We present a rare case of PEG interferon-induced dilated cardiomyopathy. A 65-year-old female with hepatitis C (HCV), mononeuritis multiplex, mixed cryoglobulinemia, and hypertension presented with complaints of shortness of breath with minimal exertion, which was gradually worsening. She denied any chest pain, palpitations, fever, chills, blood loss, weight loss, or history of smoking. She was started on treatment for HCV in June of 2012, with telapravir, PEG interferon, and ribavirin. Her viral load was detectable at week four, and undetectable at weeks 12 and 24. Her renal function was normal at the start of treatment. During the therapy, her renal function started to deteriorate. Doses of ribavirin and interferon were reduced secondary to her anemia and neutropenia, respectively. Despite dose reduction, treatment was stopped at week 33 due to treatment intolerance. Prior to treatment, the patient had a cardiac catheterization, which showed an ejection fraction (EF) of 50% and non-obstructive coronary artery disease. An echocardiogram done in following treatment showed an EF of 30-35%, with moderate mitral regurgitation (MR) and global left ventricular hypokinesia, stage three diastolic dysfunction, left ventricular dilatation, moderate left atrial dilatation, trace tricuspid regurgitation, and a pulmonary artery pressure of 40 mmHg. A transesophageal echocardiogram (TEE) confirmed the global hypokinesia, and the EF had decreased to 15-20%, with moderate MR. Repeat cardiac catheterization showed global hypokinesia, patent coronary arteries, and an EF of 25-30%. The right ventricular systolic pressure was 41 mmHg. Cryoglobulins were absent, and the rheumatoid factor had decreased to 45 from 200 prior to treatment. An autoimmune work-up was negative. The patient denied any flu-like illness during treatment. A myocardial biopsy was not performed to confirm the diagnosis; however, after ruling out other causes of cardiomyopathy, we attributed the cardiomyopathy to interferon therapy. We believe that the deterioration in renal function may have caused elevated concentrations of interferon, resulting in cardiotoxicity. The sudden worsening of the cardiomyopathy and its chronology in relation to the use of pegylated interferon and deteriorating renal function further support our impression.

Diagnostics and Treatment of Cryoglobulinaemia: It Takes Two to Tango

Cryoglobulins are immunoglobulins that reversibly precipitate in the cold. They come in different flavours and, as such, are differentially associated with lymphoproliferative diseases (type I), or systemic autoimmune diseases, and/or infectious diseases (type II/III). The clinical manifestations of cryoglobulinaemia result from either hyper-viscosity or small vessel vasculitis. Hepatitis C virus (HCV) is a well-known factor in the aetiology of cryoglobulinaemia, but substantial geographical differences exist in the association between cryoglobulins and HCV. In the absence of any underlying disease, cryoglobulinaemia is referred to as 'idiopathic' or 'essential'. Detection of cryoglobulins in the laboratory is hampered by several pitfalls, in particular in the pre-analytical stage as well as in the quantification. In addition, our personal experience reveals that the detection of rheumatoid factor, most often present in high concentrations in patients with mixed cryoglobulinaemia, relies on the choice of the test system. Hence, interpretation of the laboratory results in relation to the clinical manifestations requires a partnership between the clinician and the laboratory specialist in order to make a correct diagnosis. Treatment options are primarily directed by identification of underlying diseases, i.e. infections or systemic autoimmune diseases. Idiopathic cryoglobulinaemia is treated with corticosteroids and immunosuppression, or B cell depleting anti-CD20 biologicals. In this overview, the recent literature on current laboratory and clinical practice of cryoglobulinaemia is discussed from a personal perspective.

Impact of Cryoglobulinemic Syndrome on the Outcome of Chronic Hepatitis C Virus Infection

We evaluated the influence of cryoglobulinemic syndrome (CS) on the outcome of chronic hepatitis C virus (HCV) infection in a 15-year prospective study. We assessed a cohort of 950 chronically HCV-infected patients, collected from the beginning of 1990 to the end of 2010. All patients had received a liver histologic diagnosis. Mixed cryoglobulinemia (MC) was determined in 246 patients (25.8%), of whom 184 also had CS. They were assessed every 3 months for 15 years, at least; 141 patients with CS and 601 without MC completed the study.No spontaneous clearance of cryoglobulins was noted. Type II to type III spontaneous switching was ascertained in 1.6% (0.08%/yr) patients. The estimated progression rate of liver fibrosis was lower in CS(+) than in MC(−) patients (p < 0.05). The 15-year cumulative probability of developing cirrhosis and/or hepatocellular carcinoma was higher in MC(−) than in CS(+) patients (24.9% vs. 14.2%, p < 0.005 and 20.3% vs. 7.5%, p = 0.003, respectively). Renal insufficiency, neurologic impairment, or B-cell non-Hodgkin lymphoma were significantly more frequent in CS(+) than in MC(−) patients (32.6% vs. 3%, p < 0.0001; 31.2% vs. 4.8%, p < 0.0001; and 15% vs. 7.1%, p = 0.003, respectively). However, in spite of different morbidity features and causes of death, the 15-year survival rate was similar in the 2 groups (70.2% vs. 71.7%). Antiviral therapy had an undisputable impact on patient outcome.This 15-year prospective cohort study shows that, although CS has no influence on the overall survival of HCV-infected patients, it significantly modifies the natural history of chronically HCV-infected patients.

Long-term remission with rituximab in a patient with severe hepatitis C virus-induced mixed cryoglubulinemia

Mixed cryoglobulinemia (MC) is a small-vessel systemic vasculitis characterized by the presence of cryoglobulins, immunoglobulin complexes that precipitate at low temperatures ( < 37 ºC) inducing the inflammatory process. The most frequent etiology is hepatitis C infection (HCV) (1). Rituximab (RTX), an anti-CD20 monoclonal antibody, has recently emerged as the treatment of choice for severe MC (2). We present a case of severe hepatitis C virus-induced MC that was controlled and maintained in remission with RTX for 26 months, a remarkable prolonged period of time.

Somatic Hypermutations Confer Rheumatoid Factor Activity in Hepatitis C Virus–Associated Mixed Cryoglobulinemia

Hepatitis C virus (HCV) is the most frequent cause of mixed cryoglobulinemia (MC), which is characterized by endothelial deposition of rheumatoid factor (RF)-containing immune complexes and end-organ vasculitis. MC is a lymphoproliferative disorder in which B cells express RF-like Ig, yet its precise antigenic stimulus is unknown. We have proposed that IgG-HCV immune complexes stimulate B cell expansion and somatic hypermutation (SHM)-induced affinity maturation in part via engagement of an RF-like B cell receptor. This study was undertaken to test the hypothesis that SHM augments RF activity. RFs cloned from single B cells from 4 patients with HCV-associated MC (HCV-MC) were expressed as IgM, IgG, or IgG Fab. Selected Ig were reverted to germline. RF activity of somatically mutated Ig and germline-reverted Ig was determined by enzyme-linked immunosorbent assay. Ig with SHM had RF activity, with the preference for binding being highest for IgG1, followed by IgG2 and IgG4, and lowest for IgG3, where there was no detectable binding. In contrast, reverted germline IgG exhibited markedly diminished RF activity. Competition with 1 μg/ml of protein A abrogated RF activity, suggesting specificity for IgG Fc. Swapping of mutated heavy-chain pairs and light-chain pairs also abrogated RF activity, suggesting that context-specific pairing of appropriate IgH and Igκ, in addition to SHM, is necessary for RF activity. SHM significantly contributes to RF activity in HCV-MC patients, suggesting that autoreactivity in these patients arises through antigen-dependent SHM, as opposed to nondeletion of autoreactive germline Ig.

Increased CXCL9 Serum Levels in Hepatitis C-Related Mixed Cryoglobulinemia, with Autoimmune Thyroiditis, Associated with High Levels of CXCL10

Until now, no study has evaluated CXCL9 in hepatitis C virus (HCV) infection-related mixed cryoglobulinemia (MC) patients in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCL10 have been measured in 60 patients with MC (MCo), in 35 patients with MC and AT (MC-AT), in sex and age-matched controls: 60 healthy (Control 1); 35 patients with AT without cryoglobulinemia (Control 2). CXCL9 and CXCL10 were higher in MC-AT patients than Control 2 (P<0.0001) and MCo (P=0.01), in MCo than Control 1 (P<0.0001), and in Control 2 than Control 1 (P<0.001). By defining a high CXCL9 level as a value>2 SD above the mean value of the Control 1 (>122 pg/mL), 5% of Control 1, 34% of Control 2, 91% of MCo, and 97% of MC+AT had high CXCL9 (P<0.0001, chi-square). By simple regression analysis CXCL9 and CXCL10 were related to each other in MCo (r=0.426, P=0.001) and in MC-AT (r=0.375, P=0.001). We first demonstrate high serum levels of CXCL9 in cryoglobulinemic patients, especially with AT. Further, a strong association between serum CXCL9 and CXCL10 has been observed in patients with MC in presence/absence of AT.

HCV-related autoimmune disorders in HCV chronic infection.

Patients with hepatitis C virus (HCV) chronic infection may develop a great number of extrahepatic manifestations. Among these latter, mixed cryoglobulinemia (MC) represents the prototype of HCV-associated autoimmune-lymphoproliferative disorders. Other rheumatological manifestations of HCV chronic infection are Siögren syndrome, arthritis and CREST syndrome. Thyroid autoimmune disorders are among the most frequent manifestations of HCV chronic infections and are clinically relevant because of the association with thyroid dysfunctions and hypothyroidism. Autoimmune cytopenia is also reported in association with HCV infection. This paper reviews the association of HCV chronic infection with the above mentioned pathologies, and their immunopathogenesis.