key: cord-0001620-0go1vl9q authors: Fallahi, Poupak; Ferrari, Silvia Martina; Politti, Ugo; Giuggioli, Dilia; Ferri, Clodoveo; Antonelli, Alessandro title: Autoimmune and Neoplastic Thyroid Diseases Associated with Hepatitis C Chronic Infection date: 2014-10-13 journal: Int J Endocrinol DOI: 10.1155/2014/935131 sha: 5bae3e47050469780ae94d2f254ab80221178ebf doc_id: 1620 cord_uid: 0go1vl9q 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. About 130-170 million people worldwide have been infected by hepatitis C virus (HCV) [1] . Hepatocytes represent the major site of viral replication, and the replication of HCV is present in extrahepatic tissues and peripheral blood mononuclear cells [2] . Previous studies have shown that 38-76% of patients with chronic HCV infection develop at least one extrahepatic manifestation (EHM) [3, 4] . An association between HCV and mixed cryoglobulinemia (MC) was first described; subsequently, the involvement of many organs and systems was reported (kidney, skin, eyes, joints, and nervous system). The infected extrahepatic tissues might act as a reservoir for HCV [5] and play a role in both HCV persistence and reactivation of infection. HCV, as an etiological agent replicating and expressing viral proteins in extrahepatic tissues itself, contributes to EHM associated with chronic HCV infection. An important feature of HCV is that the virus avoids immune elimination; a consequence is chronic infection and an accumulation of circulating immunocomplexes and autoimmune phenomena [6] [7] [8] , as recently Cheng et al. have demonstrated in their study among 297 Chinese patients [9] . These EHM mainly include autoimmune disorders [10] [11] [12] such as MC [13, 14] and Sjogren's syndrome and endocrinological diseases as autoimmune thyroid disorders (AITD) and type 2 diabetes [15] [16] [17] . 2 International Journal of Endocrinology definitely more frequent in female gender and in the elderly. The incidence in female gender is of 3,5 cases/1000 subjects per year, while in men it is lower (0,8 cases/1000 persons per year): there is a remarkable variability in different geographic areas [18] . AT is an organ-specific autoimmune disease, morphologically characterized by a chronic lymphocytes infiltration of thyroid and the presence of circulating autoantibodies such as antiperoxidase (AbTPO) and antithyroglobulin (AbTg). The inflammatory process leads to a follicular destruction; indeed, AT is the most common cause of hypothyroidism in areas of iodine sufficiency [19] . Occasionally, thyroid stimulating hormone (TSH) receptor blocking antibodies can be responsible of an atrophic form of AT; more rarely, anti-TSH receptor stimulating antibodies can cause a transient form of hyperthyroidism (hashitoxicosis) [20] . Risk factors associated with AT are numerous [21] [22] [23] [24] . (a) Age: the prevalence of disease tends to increase with age. (b) Genetic: a significant association between Hashimoto's thyroiditis and some histocompatibility antigens (HLA-DR, HLA-DR5, and some DQ alleles) is demonstrated. Many other susceptibility genes have been associated with AT; for example, specific CTLA4 gene polymorphisms are linked to a possible development of antithyroid antibodies [25] . (c) Iodine: an increased AT prevalence is observed in areas of iodine sufficiency, compared with iodinedeficient areas [26, 27] . (d) Selenium: a selenium deficit is linked to a higher AT prevalence [28] . (e) Irradiation: AT occurs more frequently after the exposure to low doses of radiations [26] . (f) Cytokine: the treatment with Interferon-(IFN-) , or with Interleukin-(IL-) 2, can promote the onset of AT in predisposed patients [29] . (g) Infections: it was seen that several viral infections can predispose to an AT in animals. Moreover, different studies tried to associate AT with viral infections in humans with conflicting results [30] [31] [32] [33] . Autoimmunity. In a first study, Tran et al. report two cases of Hashimoto's thyroiditis associated with chronic active HCV infection, suggesting that HCV infection might be involved in the appearance of AT [34, 35] . The prevalence of HCV infection in patients with different thyroid disorders has been evaluated by several studies with conflicting results. Duclos-Vallée et al. evaluated the prevalence of HCV infection in 200 patients with thyroid diseases; among 50 patients with simple goiter, none were anti-HCV-positive; among 50 individuals with goiter, 2 were positive; among 5 individuals with myxedema, 2 were positive; among 50 patients with Hashimoto's thyroiditis, 12 were positive. These results suggested that HCV infection might be associated with AT [36] . Recently, Yang et al. compared 462 persons with positive AbTPO and/or AbTg to 360 persons with antibody negativity and no difference in the prevalence of anti-HCV positivity between the 2 groups (1.3% versus 0.53%; > 0.05) was found [37] . In a study conducted by Marconcini et al., 66 HCV+ patients were evaluated and AbTPOs were detected in 4/54 (7.4%) of the patients, whereas AbTgs were detected in none of the patients (0/48) [38] . Conflicting results have been reported from earlier studies of patients with CHC, with some supporting an association of HCV infection with AITD [39] [40] [41] [42] [43] [44] [45] [46] [47] and others not [48, 49] . However, some of the earlier studies were negative because of the lack of control for factors which may affect the development of thyroid autoimmunity, such as iodine intake [50] . Indeed, the largest study about HCV and thyroiditis, in which iodine deficiency was evaluated, demonstrated that both hypothyroidism and thyroid autoimmunity were significantly more common in patients with HCV compared to controls [41] . The prevalence of thyroid disorders in 630 consecutive patients with chronic hepatitis due to HCV infection was investigated; all patients were free of cirrhosis and hepatocarcinoma and were not on interferon treatment. Three control groups were included: (a) 389 subjects from an iodine-deficient area, (b) 268 persons living in an area of iodine sufficiency, and (c) 86 patients > 40 years of age with chronic hepatitis B. Levels of thyroid-stimulating hormone (TSH), free T4 (FT4), and free T3 (FT3), as well as AbTgs and AbTPOs, were measured. Mean TSH levels were higher ( = 0.001) and FT3 and FT4 levels were lower ( < 0.0001) in patients with CHC than in all other groups. Patients with CHC were more likely to have hypothyroidism (13% ( = 82)), AbTgs (17% ( = 108)), and AbTPOs (21% ( = 132)) than were any of the other groups. The results of this study suggested that both hypothyroidism and thyroid autoimmunity are more common in patients with CHC, even in the absence of cirrhosis, hepatocellular carcinoma, or interferon treatment, than in HCV-negative controls or in patients with chronic hepatitis B infection [41] . Evidence for this association also came from a study that reported a higher prevalence of hypothyroidism and AbTgs in untreated children with CHC compared to healthy non-HCV infected controls [51] . In most studies, examining the frequency of thyroid disorders in patients with HCV, approximately 10-15% of the patients had positive thyroid antibodies before the beginning of the therapy with IFN [52] [53] [54] [55] [56] [57] [58] . Moreover, pooling of data from controlled studies on HCV infection and thyroid autoimmunity demonstrated a significant increase in the risk of thyroiditis in HCV patients [59] . A large study which included 146394 patients infected with HCV confirmed these results showing a significant increased risk for thyroiditis [60] . This was a retrospective cohort study of users of US Veterans Affairs health care facilities from 1997 to 2004, which included 146394 CHC patients International Journal of Endocrinology 3 who had at least 2 visits and 572293 patients uninfected with HCV. The thyroiditis risk was significantly increased in HCV patients. Since 97% of HCV patients were men and it is well known that male gender has a lower risk of thyroiditis than female, this result is particularly interesting [60] . The presence of higher risk of AT in female gender increased circulating levels of AbTPOs and increased risk of hypothyroidism in female gender and AbTPO-positive subjects characterized the pattern of thyroid disorders observed in HCV infection [59, 61, 62] . Despite their remarkable therapeutic efficacy, IFNadverse effects are well-known, from influenza-like symptoms to hematologic effects, neuropsychiatric symptoms, and thyroid diseases [63] . In particular, previous studies showed that female gender is one of the most common risk factors that predict the development of AITD during interferon therapy [64, 65] . An association between IFNand thyroid disease was recognized as early as 1985 in patients who have been treated with IFN-for breast cancer [66] . Later, several cases have reported the possible association between thyroid disease and IFN- [67] . Different forms of IFN induced thyroid autoimmunity have been identified, such as GD, thyroiditis, and subclinical hypothyroidism [68] . Graves' hyperthyroidism is the less common type, because only 20-25% of all patients with IFN-related thyrotoxicosis are linked to Graves' disease (GD) induced by circulating thyroid receptor antibodies (TRAb) [69, 70] . Interferon induced thyroiditis (IIT) can be divided into two main groups: autoimmune type and nonautoimmune type [71] . The former can manifest as HT and GD and sometimes may be related to the production of thyroid autoantibodies without clinical disease. Another interesting classification of interferon induced hyperthyroidism has been proposed by Czarnywojtek et al. [72] (in comparison with amiodarone induced thyrotoxicosis (AIT)): (I) type 1, corresponding to type I amiodarone induced thyrotoxicosis (AIT): (a) GT without TAO and (b) GT with TAO (mild or severe); (II) type 2 destructive thyrotoxicosis, partially analogous to type II AIT: (a) asymptomatic: silent thyroiditis and (b) symptomatic; and (III) type 3 unknown aetiology, partial analogy to type III AITundefined or mixed. The presence of thyroid autoantibodies before the initiation of IFN-therapy is an important risk factor for the development of IIT. In HCV-positive individuals, the progression toward hypothyroidism, in thyroid autoantibodies positive patients who undergo IFN-treatment, is often associated with an increase in antibody titers [73] . Furthermore, Prummel and Laurberg showed that positive pretreatment AbTPOs are an important risk factor for the development of thyroid dysfunction [74] . There is also an obvious link between female sex, old age, and genetic predisposition with the development of antibodies [75, 76] . Few anecdotal studies evaluated AITD in patients with cryoglobulinemia [77, 78] . A case-control prospective study has been conducted to evaluate thyroid disorders in 93 MC + HCV patients, matched by sex and age (±2 years), to 93 patients with CHC without MC and 93 healthy (HCV-negative) controls from the local population [79, 80] . The following thyroid autoimmune abnormalities were significantly more frequent in MC + HCV patients than in HCV-negative controls: serum AbTPO levels (28% versus 9%), serum AbTPO and/or AbTg levels (31% versus 12%), AT (35% versus 16%), and subclinical hypothyroidism (11% versus 2%). Serum AbTPOs were also significantly more frequent in MC + HCV patients than in CHC controls (28% versus 14%). A higher prevalence of thyroid disorders in patients with MC + HCV not only with respect to controls, but also with respect to HCV patients without cryoglobulinemia was shown, suggesting a careful monitoring of thyroid function in these patients [80] . The presence of a higher risk of AT and hypothyroidism and increased circulating levels of AbTPO, in female gender, characterized the pattern of thyroid disorders observed in MC + HCV infection, similarly to HCV patients without MC [59, 61] . A high prevalence of papillary thyroid cancer (PTC) was first observed in 139 HCV patients (2.2%), while no case was observed in 835 control subjects who were long-term residents of an iodinedeficient area [81] , and it was subsequently confirmed in other studies [82, 83] . Montella Risks were greater for liver cancer (OR = 32.9, 95% CI 16.5-65.4, < 0.0001), multiple myeloma (OR = 4.5, 95% CI 1.9-10.7, = 0.0004), and B-cell non-Hodgkin's lymphoma (OR = 3.7, 95% CI 1.9-7.4, = 0.0001). For Hodgkin's disease, there was no significant association ( = 0.3). An association between HCV and thyroid cancer was noted (OR = 2.8, 95% CI 1.2-6.3, = 0.01) [83] . The prevalence of thyroid cancer was also investigated in a series of unselected 94 MC + HCV patients in comparison with a gender-and age-matched control group obtained from a sample of the general population (470 subjects). The prevalence of thyroid nodules was higher in control subjects than in MC + HCV patients (65.3% versus 54.8%), even though not significantly. Two patients with PTC were found in the MC + HCV series, while no case was observed among controls ( = 0.001). Lymphocytic infiltration was observed in the thyroid tissue in both MC + HCV patients with PTC [84] . Other studies have confirmed an association between AT and thyroid cancer [85, 86] . Accordingly, features of AT were observed more frequently in HCV patients than in controls suggesting that AT may be a predisposing condition for thyroid cancer [87] . Since about 15-30% of HCV patients may show an aggressive disease, for example, lung metastases, difficult to treat [88, 89] , the finding of an 4 International Journal of Endocrinology increased prevalence of thyroid cancer in these patients is clinically relevant [90] . Several molecular mechanisms have been suggested for the association of CHC with AT: (a) molecular mimicry or cross-reactivity which may occur between viral antigens and thyroidal antigens [91] , (b) heat shock proteins expression in thyroid gland [92] , and (c) abnormal expression of MHC class II molecules by thyrocytes [93] . An increased expression of IFN-and IFN-inducible chemokines [94, 95] , in particular (C-X-C motif) ligand 10 chemokine (CXCL10), has been shown in hepatocytes and in lymphocytes of HCV infected patients, directly related to the degree of inflammation and to an increase in circulating levels of IFN-and CXCL10 [40, [96] [97] [98] [99] [100] [101] [102] [103] . CXCL10 is one of chemokines with C-X-C motif. IP-10 activates specifically CXCR3 receptor that is a G protein-coupled receptor with seven transmembrane domains mainly expressed in T activated lymphocytes, natural-killer cells (NKs), macrophages, and B cells [104, 105] . Recent studies showed that CXCL10 expression in serum and/or tissue levels is increased in autoimmune organ-specific diseases [106] , such as type 1 diabetes [107] [108] [109] , or systemic rheumatological diseases like rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis [97, 110] , sarcoidosis [111, 112] , and psoriatic arthritis [113, 114] . High levels of CXCL10 are present in patients with AT, in particular in the presence of hypothyroidism, and an involvement of T-helper (Th)1 immune response in the induction of AT [97, [115] [116] [117] , GD, and Graves' ophthalmopathy [97] [98] [99] [100] 118] has been demonstrated, suggesting that intrathyroidal lymphocytes and/or thyrocytes may be the source of CXCL10 [119] . Furthermore, the presence of HCV in the thyroid of chronically infected patients has been recently shown [120, 121] . On the abovementioned bases, it has been speculated that HCV thyroid infection may act by upregulating CXCL10 gene expression and secretion in thyrocytes recruiting Th1 lymphocytes that secrete IFN-and tumor necrosis factor-(TNF-) . These cytokines induce CXCL10 secretion by thyrocytes, thus perpetuating the immune cascade, which may lead to the appearance of AITD in genetically predisposed subjects [111] ( Figure 1) . Recently, the finding of high serum levels of CXCL10 but normal levels of the prototype Th2 chemokine (C-C motif) ligand 2 (CCL2) in MC + HCV patients with AT, in comparison with patients without thyroiditis, has confirmed this hypothesis. These data suggest that the Th1 CXCL10 chemokine is specifically linked to the appearance of AT in these patients [122] . Serums CXCL10 and CCL2 were assayed in 60 MC + HCV patients, in 45 patients with "MC with AT" (MC + AT), and in controls (60 without (control 1) and 45 with AT (control 2)). CXCL10 was significantly higher in control 2 than in control 1 ( < 0.001), in MC than in control 1, and in MC + AT than in controls 1 and 2 and MC ( = 0.002). A high CXCL10 level (>mean ± SD control 1; >167 pg/mL) was present in 7% of control 1, 21% of control 2, 49% of MC, and 78% of MC + AT ( < 0.0001). CCL2 was significantly higher in MC and in MC + AT than in control 1 or in control 2 ( < 0.01). A high CCL2 level (>mean ± SD control 1; >730 pg/mL) was present in 2% of control 1, 1% of control 2, 18% MC, and 21% of MC + AT ( < 0.0001) [122] . Among the proinflammatory cytokines, IL-1 and TNFwere not associated with the presence of AT in MC + HCV patients, while IL-6 was modestly but significantly increased in patients with AT [5, [123] [124] [125] . On the whole, in agreement with what was observed in other autoimmune disorders [126] [127] [128] [129] , the above reported data underline the importance of the activation of the Th1 immunity in the initiation of AT in patients with MC + HCV. In conclusion, the abovementioned results show a high prevalence of AITD in patients with CHC infection. The presence of a higher risk of AT in female gender, increased circulating levels of AbTPOs, and increased risk of hypothyroidism in female gender and AbTPO-positive subjects characterized the pattern of thyroid disorders observed in HCV infection. In HCV patients with thyroid cancer, thyroidectomy is required and, if appropriate, radioiodine treatment. Patients with HCV infection with AITD where nodules occurred and in fine needle aspiration biopsy without neoplastic processes do require careful observation. Epidemiology of hepatitis C virus infection Extrahepatic replication of HCV: insights into clinical manifestations and International Journal of Endocrinology 5 biological consequences Chronic hepatitis C virus infection: prevalence of extrahepatic manifestations and association with cryoglobulinemia in Bulgarian patients Extrahepatic manifestations of chronic HCV infection B-cells and mixed cryoglobulinemia HCV-related autoimmune and neoplastic disorders: the HCV syndrome HCV-related autoimmune disorders in HCV chronic infection Mixed cryoglobulinemia and thyroid autoimmune disorders Extrahepatic manifestations of chronic hepatitis C virus infection: 297 cases from a tertiary medical center in Beijing, China Hepatitis C virus infection of a thyroid cell line: implications for pathogenesis of hepatitis C virus and thyroiditis Autoantibodies in patients with chronic hepatitis C virus infection: pitfalls for the diagnosis of rheumatic diseases Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation Prevalence and risk factors for the presence of serum cryoglobulins in patients with chronic hepatitis C Cryoglobulinemia in chronic liver diseases: Role of hepatitis C virus and liver damage Hepatitis c virus and type 1 diabetes Hepatitis C virus infection and type 2 diabetes Hepatitis C and D, retroviruses and autoimmune manifestations The incidence and prevalence of thyroid autoimmunity Thyroid autoimmunity Hashimoto thyroiditis: clinical and diagnostic criteria Type 1 diabetes and (C-X-C motif) ligand (CXCL) 10 chemokine The alpha chemokine "Interferon gamma-induced protein 10 Why is the thyroid so prone to autoimmune disease? Environmental exposures and autoimmune thyroid disease Genetic susceptibility to autoimmune thyroid disease: past, present, and future Environmental factors and thyroid autoimmunity Is humoral thyroid autoimmunity relevant in amiodarone iodine-induced thyrotoxicosis (AIIT)? Current Opinion in Endocrinology Hepatitis C: thyroid dysfunction in patients with hepatitis C on IFN-therapy Viruses and thyroiditis: an update HCV E2 protein binds directly to thyroid cells and induces IL-8 production: a new mechanism for HCV induced thyroid autoimmunity Effects of excess iodine administration on thyroid function in euthyroid patients with a previous episode of thyroid dysfunction induced by interferon-alpha treatment Infection, thyroid disease, and autoimmunity Detection of hepatitis C virus in thyroid tissue from patients with chronic HCV infection Extrahepatic disease manifestations of HCV infection: some current issues High prevalence of serum antibodies to hepatitis C virus in patients with Hashimoto's thyroiditis Prevalence of thyroid autoantibodies in hepatitis C and hepatits B infection in China Autoantibody profile in individuals with chronic hepatitis C Increased risk of autoimmune thyroid disease in hepatitis C vs hepatitis B before, during, and after discontinuing interferon therapy Thyroid disturbance related to chronic hepatitis C infection: role of CXCL10 Thyroid disorders in chronic hepatitis C Thyroid dysfunction (TD) among chronic hepatitis C patients with mild and severe hepatic fibrosis HCV and autoimmunity Environmental triggers of thyroiditis: hepatitis C and interferon Prevalence of HCV antibodies in autoimmune thyroid disease Endocrine manifestations of hepatitis C virus infection Failure to find an association between hepatitis C virus and thyroid autoimmunity Prevalence of thyroid autoantibodies is not increased in blood donors with hepatitis C virus infection Latent autoimmune thyroiditis in untreated patients with HCV chronic hepatitis: a case-control study Clinical picture of endemic cretinism in central Apennines (Montefeltro) Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection Latent autoimmune thyroid disease in patients with chronic HCV hepatitis The risk factor for development of thyroid disease during interferon-therapy for chronic hepatitis C Longitudinal study of antibodies against thyroid in patients undergoing interferontherapy for HCV chronic hepatitis Multiple changes in thyroid function in patients with chronic active HCV hepatitis treated with recombinant interferon-alpha Thyroid autoimmune disorders in patients with chronic hepatitis C before and during interferon-therapy The addition of ribavirin to interferon-therapy in patients with hepatitis C virus-related chronic hepatitis does not modify the thyroid autoantibody pattern but increases the risk of developing hypothyroidism Clinical observation of Hashimoto thyroiditis in patients with chronic hepatitis C undergoing pegylated-interferon alpha-2a and ribavirin combination therapy Thyroid disorders in chronic hepatitis C virus infection Risk of non-Hodgkin lymphoma and lymphoproliferative precursor diseases in US veterans with hepatitis C virus HCV infection: pathogenesis, clinical manifestations and therapy Subclinical autoimmune thyroid disorders in Egyptian patients with untreated chronic hepatitis C virus infection Side effects of therapy for chronic hepatitis C Thyroid dysfunction during treatment of chronic hepatitis C with interferon alpha: No association with either interferon dosage or efficacy of therapy Thyroid function and changes in ultrasound morphology during antiviral therapy with pegylated interferon and ribavirin in patients with chronic hepatitis C Primary hypothyroidism associated with interferon therapy of breast cancer A meta-analysis of patients with chronic hepatitis C treated with interferon-alpha to determine the risk of autoimmune thyroiditis The spectrum of autoimmune thyroid disease in the short to medium term following interferon-therapy for chronic hepatitis C Interferoninduced thyroid dysfunction: three clinical presentations and a review of the literature Thyrotoxicosis induced by alpha-interferon therapy in chronic viral hepatitis The clinical and physiological spectrum of interferon-alpha induced thyroiditis: Toward a new classification Patients with chronic hepatitis type C and interferonalpha-induced hyperthyroidism in two-years clinical followup Thyroid dysfunction in hepatitis C individuals treated with interferon-alpha and ribavirin-a review Interferon-and autoimmune thyroid disease Interferon alpha-Induced hashimoto thyroiditis followed by transient graves disease in a patient with chronic HCV infection Patterns of interferon-alpha-induced thyroid dysfunction vary with ethnicity, sex, smoking status, and pretreatment thyrotropin in an international cohort of patients treated for hepatitis C Thyroid-stimulating immunoglobulins in mixed (type II) cryoglobulinemia associated with thyrotoxicosis Hypotiroidism, hemolytic anemia and cryoglobulinemia in a patient with hepatitis C virus infection: efficacy of treatment with alpha-interferon High values of CXCL10 serum levels in mixed cryoglobulinemia associated with hepatitis C infection Thyroid involvement in patients with HCV-related mixed cryoglobulinaemia Thyroid cancer in patients with hepatitis C infection Is hepatitis C virus infection associated with thyroid cancer? A case-control study HCV and cancer: a case-control study in a high-endemic area Thyroid cancer in HCV-related mixed cryoglobulinemia patients Hashimoto's thyroiditis is associated with papillary thyroid carcinoma: role of TSH and of treatment with L-thyroxine Chronic hepatitis C virus infection increases mortality from hepatic and extrahepatic diseases: a community-based long-term prospective study Thyroid cancer in HCVrelated chronic hepatitis patients: a case-control study Pulmonary function, smoking habits, and high resolution computed tomography (HRCT) early abnormalities of lung and pleural fibrosis in shipyard workers exposed to asbestos Dedifferentiated thyroid cancer: a therapeutic challenge Novel pyrazolopyrimidine derivatives as tyrosine kinase inhibitors with antitumoral activity in vitro and in vivo in papillary dedifferentiated thyroid cancer Amino acid sequence homologies between HCV polyprotein and thyroid antigens Hepatitis C and thyroid autoimmunity: is there a link? Interferon alpha treatment and thyroid dysfunction Enhanced expression of interferon-regulated genes in the liver of patients with chronic hepatitis C virus infection: detection by suppression-subtractive hybridization Expression of the chemokine IP-10 correlates with the accumulation of hepatic IFN-and IL-18 mRNA in chronic hepatitis C but not in hepatitis B Chemokine (C-X-C motif) ligand (CXCL)10 in autoimmune diseases CXCR3, CXCL10 and type 1 diabetes Increase of interferon--inducible CXC chemokine CXCL10 serum levels in patients with active Graves' disease, and modulation by methimazole therapy Iodine-131 given for therapeutic purposes modulates differently interferon--inducible -chemokine CXCL10 serum levels in patients with active Graves' disease or toxic nodular goiter Serum levels of the interferon--inducible chemokine CXCL10 in patients with active Graves'disease, and modulation by methimazole therapy and thyroidectomy Increase of CXC chemokine CXCL10 and CC chemokine CCL2 serum levels in normal ageing Exploiting hepatitis C virus activation of NF B to deliver HCV-responsive expression of interferons and Increased frequency of IFN--producing peripheral CD8 + T cells with memory-phenotype in patients with chronic hepatitis C Lymphocyte-specific chemokine receptor CXCR3: regulation, chemokine binding and gene localization The chemokine receptors CXCR3 and CCR5 mark subsets of T cells associated with certain inflammatory reactions High pretransplant serum levels of CXCL10/IP-10 are related to increased risk of renal allograft failure Autoantibodies to CD38 (ADP-ribosyl cyclase/cyclic ADP-ribose hydrolase) in Caucasian patients with diabetes: effects on insulin release from human islets Autoimmunity to CD38 and GAD in type I and type II diabetes: CD38 and HLA genotypes and clinical phenotypes Human anti-CD38 autoantibodies raise intracellular calcium and stimulate insulin release in human pancreatic islets CXCL10 ( ) and CCL2 ( ) chemokines in systemic sclerosis-a longitudinal study Prevalence of hypothyroidism and Graves disease in sarcoidosis Elevated serum levels of CXCL9/monokine induced by interferon-and CXCL10/interferon--inducible protein-10 in ocular sarcoidosis High prevalence of thyroid autoimmunity and hypothyroidism in patients with psoriatic arthritis High values of alpha (CXCL10) and beta (CCL2) circulating chemokines in patients with psoriatic arthritis, in presence or absence of autoimmune thyroiditis Monokine induced by interferon (IFN ) (CXCL9) and IFN inducible T-cell -chemoattractant (CXCL11) involvement in Graves' disease and ophthalmopathy: modulation by peroxisome proliferator-activated receptor-agonists Anti-CD38 autoimmunity in patients with chronic autoimmune thyroiditis or Graves' disease Increased serum CXCL10 in Graves'disease or autoimmune thyroiditis is not associated with hyper-or hypothyroidism per se, but is specifically sustained by the autoimmune, inflammatory process Cytokine profiles in eye muscle tissue and orbital fat tissue from patients with thyroid-associated ophthalmopathy Expression of IP-10/CXCL10 and MIG/CXCL9 in the thyroid and increased levels of IP-10/CXCL10 in the serum of patients with recent-onset Graves' Disease Interferon--inducible -chemokine CXCL10 involvement in Graves' ophthalmopathy: modulation by peroxisome proliferator-activated receptor-agonists Distribution of markers of hepatitis C virus infection throughout the body Chemokine CXCL10 and -chemokine CCL2 serum levels in patients with hepatitis C-associated cryoglobulinemia in the presence or absence of autoimmune thyroiditis Interleukin-1 , C-X-C motif ligand 10, and interferon-gamma serum levels in mixed cryoglobulinemia with or without autoimmune thyroiditis The presence of autoimmune thyroiditis in mixed cryoglobulinemia patients is associated with high levels of circulating interleukin-6, but not of tumour necrosis factor-alpha Early menopause is associated with lack of response to antiviral therapy in women with chronic hepatitis C CXCR3 signaling reduces the severity of experimental autoimmune encephalomyelitis by controlling the parenchymal distribution International Journal of Endocrinology 9 of effector and regulatory T cells in the central nervous system Multiple sclerosis: a study of chemokine receptors and regulatory T cells in relation to MRI variables CXCL10 and trafficking of virus-specific T cells during coronavirus-induced demyelination What causes relapses of autoimmune diseases? The etiological role of autoreactive T cells The authors declare that there is no conflict of interests regarding the publication of this paper.