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Hepatitis C virus infection and thyroid autoimmune disorders: A model of interactions between the host and the environment

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Abstract

The hepatitis C virus (HCV) infection is an important public health problem and it is associated with hepatic and extrahepatic manifestations. Autoimmune thyroid diseases are common in HCV infected patients and the standard interferon-based treatment is associated with an increase of the immune-mediated thyroid damage. Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, focusing on the balance between the two sides of the interaction: The environment (virus infection with potential cross-reaction) and the host (susceptibility genes with consistent immune response). The spectrum of antiviral treatment for chronic HCV infection is rapidly expanding for the development of dual o triple therapy. The availability of interferon-free combined treatment with direct antiviral agents for HCV is very promising, in order to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity.

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... These extrahepatic manifestations mainly consist of autoimmune disorders, as mixed cryoglobulinemia (MC), Sjogren's syndrome, endocrinological diseases as AITD and type 2 diabetes. HCV may interfere with functions and mechanisms of self-recognition, on the immune system and in thyrocytes, destroying thyroid tissue or by the mimic of some components of the thyroid gland, in this way beginning the autoimmune disease [26]. ...
... The standard antiviral therapy with IFN-α for CHC may exacerbate or induce latent thyroid disorders, increasing the incidence of AITD and dysfunction [26]. The Bde novo^presence of anti-thyroid antibodies and overt dysfunctions in euthyroid subjects have been shown upon IFN-α therapy, suggesting this cytokine could be a direct inducer of AITD [26]. ...
... The standard antiviral therapy with IFN-α for CHC may exacerbate or induce latent thyroid disorders, increasing the incidence of AITD and dysfunction [26]. The Bde novo^presence of anti-thyroid antibodies and overt dysfunctions in euthyroid subjects have been shown upon IFN-α therapy, suggesting this cytokine could be a direct inducer of AITD [26]. The standard dual therapy with pegylated IFN-α/ribavirin has been recently changed to a triple therapy, based on new directacting antiviral drugs (DAAs) [NS3/4 A serine protease inhibitor (PI)] [26]. ...
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The presence of viruses in the thyroid has been shown, but whether they are implicated in thyroid diseases or are only spectators is under investigation. The most important candidate viruses for autoimmune thyroid disorders (AITD) are hepatitis C virus (HCV) and human parvovirus B19 (or Erythrovirus B19 or EVB19). Retrospective and prospective case–control studies conducted on pathology slides showed (by PCR, in situ hybridization or immunohistochemistry) EVB19 was present in thyroid tissues of patients with autoimmune thyroiditis (AT), Graves’ disease and thyroid cancer. Though AITD can be associated with acute EVB19 infection, it is not clear whether EVB19 could have a pathogenetic role in autoimmune thyroid diseases pathophysiology. Many studies have shown that frequently, patients with HCV chronic infection (CHC) show elevated serum anti-thyroperoxidase (TPOAb) and/or anti-thyroglobulin autoantibodies levels, ultrasonographic signs of chronic AT, and subclinical hypothyroidism. In patients with HCV-associated mixed cryoglobulinemia (MC + HCV), AITD were more prevalent with respect to controls, and also vs HCV patients without cryoglobulinemia. Papillary thyroid cancer was more prevalent in MC + HCV or CHC patients than in controls, especially in patients with AT. Recently it has been shown an elevated incidence of new cases of AT and thyroid dysfunction in MC patients. These results suggest an attentive monitoring of thyroid function and nodules in HCV patients with risk factors (female gender, a borderline high initial thyrotropin, TPOAb positivity, a hypoechoic and small thyroid) for the development of thyroid disorders.
... Extrahepatic manifestations (72,73) [mixed cryoglobulinemia (MC), endocrinological diseases (AITD and type 2 diabetes), Sjogren's syndrome] are present in about 38-76% patients with chronic hepatitis C (CHC). HCV interferes with functions and self-recognition mechanisms (in immune system or in thyrocytes) leading to destruction of thyroid and beginning the autoimmune disease (74). ...
... Among drugs, IFN-and iodine-containing drugs have been associated with AITD. The "de novo" presence of ATA and overt dysfunctions in euthyroidism have been reported upon IFN-α therapy, suggesting that it can exacerbate or induce latent thyroid disorders, inducing AITD (74). The standard dual therapy with pegylated IFN-α/ribavirin has been substituted by a triple therapy with new direct-acting antiviral drugs (NS3/4A serine protease inhibitor) (74) (with/without ribavirin), thereby ameliorating the patient compliance and decreasing the risk for thyroid autoimmunity (74). ...
... The "de novo" presence of ATA and overt dysfunctions in euthyroidism have been reported upon IFN-α therapy, suggesting that it can exacerbate or induce latent thyroid disorders, inducing AITD (74). The standard dual therapy with pegylated IFN-α/ribavirin has been substituted by a triple therapy with new direct-acting antiviral drugs (NS3/4A serine protease inhibitor) (74) (with/without ribavirin), thereby ameliorating the patient compliance and decreasing the risk for thyroid autoimmunity (74). ...
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Environmental factors are determinant for the appearance of autoimmune thyroid diseases (AITD) in susceptible subjects. Increased iodine intake, selenium, and vitamin D deficiency, exposure to radiation, from nuclear fallout or due to medical radiation, are environmental factors increasing AITD. Cigarette smoking is associated with Graves’ disease and Graves’ ophthalmopathy, while it decreases the risk of hypothyroidism and thyroid autoimmunity. Viral infections are important environmental factors in the pathogenesis of AITD, too, particularly human parvovirus B19 (EVB19) and hepatitis C virus. Among the many chemical contaminants, halogenated organochlorines and pesticides variably disrupt thyroid function. Polychlorinated biphenyls and their metabolites and polybrominated diethyl ethers bind to thyroid transport proteins, such as transthyretin, displace thyroxine, and disrupt thyroid function. Among drugs, interferon- and iodine-containing drugs have been associated with AITD. Moreover intestinal dysbiosis causes autoimmune thyroiditis. To reduce the risk to populations and also in each patient, it is necessary to comprehend the association between environmental agents and thyroid dysfunction.
... Autoimmune thyroid disease and thyroid dysfunction were described in 20%-40% and 11%-15%, respectively, of the adults with CHC receiving IFN. 6 Two more recently published studies, based on large cohorts of patients, demonstrate that adults with CHC treated with peg-IFNα and RBV present a high incidence of thyroid disease during treatment (35% 7 and 27.7%, 8 respectively) with most of them recovering after completion of therapy. The exact mechanism explaining the relation between IFN-α and thyroid disease is not clear. ...
... IFN-α modulates the production of other cytokines, like IFN-γ and IL-6, and creates an imbalance of the immune system which leads to the production of thyroid autoantibodies and to a direct disruptive effect on thyroid function, at the same time. 6,9 Untreated children with CHC are at risk of both autoimmune and nonautoimmune thyroid disease with subclinical hypothyroidism and autoimmune thyroiditis described, respectively, in 11.1% and 2.8% of treatment-naïve children with chronic infection. 10 Few data are available on the effects of the association of peg-IFNα and RBV on thyroid function and antithyroid autoimmunity in children with CHC. ...
Article
Background: Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and anti-thyroid autoimmunity in children with CHC treated with pegylated interferon-α-2b and ribavirin. Methods: 61 otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated interferon-α-2b and ribavirin and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment. Results: From baseline to the end of treatment subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17/61 (27.94%) and in 4/61 (6.6%) of the children treated, respectively, and in 5/183 (2.7%) and in none of the controls [p < 0.0001, relative risk (RR): 10.2, 95% confidence interval (CI): 3.9 to 26.5; p = 0.03, RR: 26.8, 95% CI: 1.5 to 489.1, respectively]. Twenty-four weeks after the end of treatment subclinical hypothyroidism persisted in only 4/61 (6.6%). Autoimmune thyroiditis persisted in 3/4 (75%) of the cases. Conclusions: Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated interferon-α-2b and ribavirin, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with anti-thyroid autoantibodies and thyroid dysfunction during and after pegylated interferon-α based treatment.
... HCV chronic infection is associated with a multitude of extrahepatic manifestations, either by inflammatory or autoimmune mechanisms or even by direct infection of other organs, such as the thyroid [10][11][12][13]. In fact, thyroid involvement is considered the most frequent endocrine disorder associated with HCV chronic infection; mechanisms responsible for thyroid damage are thyroid destruction induced by an increased inflammatory response (resulting in autoimmune thyroiditis) or by direct HCV infection [14,15]. ...
Article
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BACKGROUND Thyroiditis is an important extrahepatic association in chronic hepatitis C virus (HCV) infection. There have been reports of an association between SARS-CoV-2 infection and the onset or re-activation of autoimmune hypothyroidism. Therefore, we performed this prospective observational study of 42 patients with COVID-19 infection and a history of hepatitis C virus infection and thyroid disease with follow-up thyroid function and autoantibody testing. MATERIAL AND METHODS From April 2020 to October 2020, we performed a prospective observational study of patients with cured hepatitis C virus (HCV) infection and documented thyroid disease who became infected with SARS-CoV-2 (confirmed by SARS-CoV-2 RNA detection via reverse-transcription polymerase chain reaction [RT-PCT] from the upper respiratory tract, both nasal and pharyngeal swabs). Evaluation at 1 and 3 months after SARS-CoV-2 infection included serum determination of antithyroid antibodies (anti-thyroglobulin [anti-Tg] and antithyroid peroxidase [ATPO]), thyroid-stimulating hormone (TSH), free thyroxine (fT4), free triiodothyronine (fT3), and evaluation of thyroid medication, with dose adjustment if required. RESULTS One-month follow-up showed that both patients with autoimmune thyroiditis as well as patients without antibodies had increased ATPO levels. Also, levels of TSH, fT3, and fT4 were significantly decreased. At 3-month follow-up, levels of ATPO were decreased in all patient groups and the levels of thyroid hormones increased to normal values. CONCLUSIONS This study supports previous reports of an association between SARS-CoV-2 infection and thyroid dysfunction associated with thyroid autoantibodies. Thyroid function tests may be considered as part of the laboratory work-up in patients with COVID-19.
... Since the generation of autoantibodies is a consequence of specific and persistent immune response in the course of HCV infection [8], a statistically significant older CHC patients with AITD (group A) is expected (p=0.001). The higher incidence of women in group A (p=0.011) is certainly explicable by a more potent immune response caused by oestrogen [10]. However, recent literature identifies TLR7 gene on X chromosome, responsible for TLR7 receptor expression on B lymphocyte [11]. ...
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Introduction/Objective. Despite sufficiently explained pathogenesis, today autoimmune thyroid diseases (AITD) are recognized as one of extra-hepatic manifestations of systemic hepatitis C virus infection. The aim of the present study was to determine clinical characteristics and to estimate the success of pegylated interferon-α2a plus ribavirin (pegIFN-α2a + RBV) therapy in patients with AITD as an extrahepatic manifestation of chronic hepatitis C infection (CHC). Methods. This prospective study included 91 CHC patients treated with pegIFN-α2a + RBV from 2010 to 2012 (39 women and 52 men, mean age 41.6 Ѓ} 11.9). The study group (group A) consisted of 31 patients with CHC and AITD. Control group (group B) consisted of 60 patients with CHC without AITD. We analyzed clinical, biochemical, virological, and histopathological markers of CHC, as well as response and side effects of pegIFN-α2a + RBV therapy. Results. There was a statistically significant difference in sex (p = 0.011), age (p = 0.001), AST level (p = 0.013), level of gamma globulins (p < 0.001), level of IgM (p = 0.007), IgG (p < 0.001), in the success of therapy of CHC with pegIFN-α2a + RBV between the groups. Odds ratio (OR) for unfavorable outcome in group A was 4.200 [95% confidence interval (CI): 1.545–11.417]. In final multivariate logistic regression analysis in group A, the only factor predicting sustained virological response was patients’ age (OR = 0.781; 95% CI: 0.603–0.959). The main side effects in group A were interferon induced thyroiditis (IIT) (41.9% vs. 3.3%; p < 0.001) and anemia, which was the only reason for dose reduction of ribavirin (29% vs. 6.7%; p = 0.027). Conclusion. Patients with AITD as an extra-hepatic manifestation of CHC achieve poorer virological response and their antiviral therapy is inevitably followed by a manifestation of adverse effects, predominantly solvable IITs and anemia.
... In our research, we found that there was no significant difference regarding TSH and free T4, before and after treatment with new DAA. In accordance with our findings, Pastore et al. [17] suggested that the availability of interferon-free combined treatment with DAAs for HCV is very promising, to ameliorate the patient compliance and to reduce the development of thyroid autoimmunity. ...
... HCV chronic infection is associated with a multitude of extrahepatic manifestations, either by inflammatory or autoimmune mechanisms (4)(5)(6)(7) or even by direct infection of other organs, such as the thyroid. In fact, thyroid involvement is considered the most frequent endocrine disorder associated with HCV chronic infection; mechanisms responsible for thyroid damage are thyroid destruction induced by an increased inflammatory response (resulting in autoimmune thyroiditis) (8) or by direct HCV infection (9). Important similarities between HCV and COVID 19 have been studied. ...
Article
Context: As we progress into the COVID-19 pandemic, it has become apparent that this infection is associated with a multitude of systemic effects, some involving the thyroid gland. The thyroid is also frequently affected in the HCV chronic infection. Objective: The objective of this study is to determine the effects of COVID-19 infection on the presence and severity of thyroid disorders associated with chronic HCV infection, at short and mid-term follow-up. Design: We prospectively evaluated patients with documented HCV- associated thyroid disease (with sustained virologic response after antiviral therapy). Subjects and methods: The study group consisted of 42 patients with HCV- associated thyroid disease, diagnosed with COVID -19 infection between April and October 2020. We determined serum values of thyroid-stimulating hormone, freeT3, free T4, anti-thyroglobulin antibodies and anti-thyroid peroxidase antibodies at one and three months after resolution of infection and compared them to the baseline characteristics of the patient. We also evaluated the changes in thyroid substitution treatments or antithyroid drugs. Results: At baseline, out of the 42 patients, 5 presented hypothyroidism under levothyroxine substitution therapy, while 2 presented hyperthyroidism under methimazole therapy; 37 patients had positive antithyroid antibodies. At one month follow-up, we note an increase in serum values of antibodies, with a decrease in TSH, freeT3 and freeT4 levels, correlated with the severity of COVID-19 infection. Two patients required discontinuation of levothyroxine. At 3 months follow-up, lower levels of antithyroid antibodies were recorded, with an increase in TSH levels. No medication doses were adjusted at this time. Conclusion: Among the systemic effects of COVID-19, the impact of thyroid dysfunction should not be underestimated, especially in the presence of pre-existing conditions, such as HCV infection.
... Pathogenesis of HCVrelated thyroid dysfunction might be mediated by stimulation of the immune system by HCV, rather than by HCV infection itself. A potential oncogenic role of HCV through the direct infection of thyroid cells has been postulated to explain the relationship between HCV infection and the risk of papillary thyroid cancer [20]. ...
Article
Thyroid hormones are essential for the normal growth, development, and function of body organs. These hormones regulate the basal metabolic rate of all cells, including hepatocytes. A complex interplay exists between the thyroid and the liver. Thyroid dysfunction can cause liver function test abnormalities, usually reverted by normalizing thyroid status. On the other hand, liver disorders may cause thyroid function abnormalities that may or may not need to be treated. Nevertheless, the relationship between liver and thyroid is often overlooked, and thyroid function is not commonly investigated in patients with liver diseases and vice versa. Keywords: Hyperthyroidism; liver cirrhosis; hypothyroidism; hepatitis.
... Autoimmune diseases are triggered by the loss of tolerance especially, autoimmune thyroid disorders, with T lymphocytes (cellular or humoral response) or autoantibodies reacting with self-antigens. 2 Existing literature suggest that thyroid dysfunction is the most common endocrine disorder that occurs in HCV infected patients and interferon (IFN) therapy has been associated with an increase in thyroid disorders. [3][4][5][6] This is the first-ever evidence to report thyroid dysfunction in two different groups of chronic hepatitis C (CHC) patients treated with two different direct-acting antiviral (DAA) drug combinations that are sofosbuvir + ribavirin + pegylated-IFN-α and sofosbuvir + ribavirin + daclatasvir. ...
... Recent evidence in the literature analyzed critical points of the mechanisms of thyroid damage, with emphasis on the balance between the two sides of the interaction: (a) the environment (virus infection with potential crossreaction); and (b) the host (susceptibility genes with consistent immune response). 35 Some studies have reported a genetic influence (the susceptibility genes) in the development of autoimmunity. 36,37 CD40 and HLA class II have been clearly linked to TD by affecting the immune response of the host. ...
Article
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Background Previous studies have reported that hepatitis C virus infection may increase the risk of thyroid disease and even thyroid cancer, but quantitative assessments of risk were rare and the results were not consistent. The purpose of this study was to evaluate the impact of hepatitis C virus infection on thyroid disease and thyroid cancer, and to provide clues to explore their relationship. Methods A literature retrieval was performed up to August 20, 2021 in the database of PubMed, Cochrane Library, Web of Science, China National Knowledge Infrastructure, and Wang Fang. The risk of hepatitis C virus for thyroid disease or thyroid cancer was expressed with odds ratio (OR) and 95% confidence intervals (CI). Subgroup analysis was used to explore the source of heterogeneity. Eight articles (Five studies published as articles and three as abstracts) were included in this meta-analysis, with a total of 5398 controls and 1925 cases of hepatitis C. Results The results of a meta-analysis found that hepatitis C virus infection was significantly associated with an increased risk of thyroid disease (sum OR = 1.80, 95% CI = 1.54–2.10, P < 0.001, I ² = 74.3%) and thyroid cancer (sum OR = 16.74, 95% CI = 4.78–58.55, P < 0.001, I ² = 0%). Hepatitis C virus infection may increase the risk of thyroid disease and thyroid cancer. Conclusion More work is needed in the future to establish a causal role; however, an awareness of the possibility of increased risk of thyroid disease and thyroid cancer may lead to earlier diagnosis and better outcomes in patients with hepatitis C.
... In addition to hepatic complications, chronic HCV infection may have several extrahepatic consequences, including endocrine and metabolic diseases, in particular type 2 diabetes mellitus and thyroid dysfunction [104] (Table 2). Autoimmune thyroid disorders (AITD), not infrequently associated with thyroid dysfunction, can be detected in a significant proportion of chronically HCV-infected patients, before antiviral drug treatment [105]. In particular, Hashimoto's thyroiditis is the most common thyroid disorder reported in these patients [106]. ...
Article
A complex relationship exists between thyroid and liver in health and disease. Liver plays an essential physiological role in thyroid hormone activation and inactivation, transport, and metabolism. Conversely, thyroid hormones affect activities of hepatocytes and hepatic metabolism. Serum liver enzyme abnormalities observed in hypothyroidism may be related to impaired lipid metabolism, hepatic steatosis or hypothyroidism-induced myopathy. Severe hypothyroidism may have biochemical and clinical features, such as hyperammonemia and ascites, mimicking those of liver failure. Liver function tests are frequently abnormal also in hyperthyroidism, due to oxidative stress, cholestasis, or enhanced osteoblastic activity. Antithyroid drug-associated hepatotoxicity is a rare event, likely related mainly to an idiosyncratic mechanism, ranging from a mild hepatocellular damage to liver failure. Propylthiouracil-induced liver damage is usually more severe than that caused by methimazole. On the other hand, thyroid abnormalities can be found in liver diseases, such as chronic hepatitis C, liver cirrhosis, hepatocellular carcinoma, and cholangiocarcinoma. In particular, autoimmune thyroid diseases are frequently found in patients with hepatitis C virus infection. These patients, especially if thyroid autoimmunity preexists, are at risk of hypothyroidism or, less frequently, thyrotoxicosis, during and after treatment with interpheron-alpha alone or in combination with ribavirin, commonly used before the introduction of new antiviral drugs. The present review summarizes both liver abnormalities related to thyroid disorders and their treatment, and thyroid abnormalities related to liver diseases and their treatment.
Article
Introduction Autoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients’ monoinfected and coinfected HCV–HIV at baseline, during and after IFNα therapy. Methods We studied 790 HCV infected patients: G1 (monoinfected HCV: N = 580) and G2 (HCV–HIV coinfected: N = 210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy. If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. Results No difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p = 0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. Conclusion Our hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases’ applications.
Article
Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small‐vessel vasculitis that may evolve into an overt B‐cell non‐Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgMk and IgMλ heavy‐light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV‐ and 2 HBV‐related), treated with low‐dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme‐linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50% respectively; in contrast, the mean levels of FLCs, IgM HLCs and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post‐treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs and VEGF could represent the signature of “dormant” B cell clones’ activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome. This article is protected by copyright. All rights reserved
Article
The recent development of direct‐acting antiviral (DAA) drugs has revolutionized the area of hepatitis C virus (HCV) therapeutics but the efficacy and clinical outcome of interferon (IFN)‐free therapy have not been extensively studied yet. We observed a dramatic increase in hypothyroidism among patients treated with sofosbuvir, IFN, and ribavirin. This is the first prospective study of the thyroid dysfunction in DAA drugs treated patients. This study compared the risk of hypothyroidism in two different groups of HCV patients treated with different DAA drugs regimens that were sofosbuvir + pegylated‐IFN‐α + ribavirin and sofosbuvir + daclatasvir + ribavirin. Our findings highlight the periodic screening of serum thyroid‐stimulating hormone and T4 levels in HCV infected patients during the treatment and posttreatment. Highlights • A mathematical model with threshold behavior in recovery and asymptomatic patients. • The efficacy and clinical outcome of interferon‐free therapy have not been extensively studied yet. • Existing literature suggest that thyroid dysfunction is the most common endocrine disorder that occurs in HCV infected patients and interferon therapy has been associated with an increase in thyroid disorders. • Our findings highlight the need of periodic screening of serum TSH and T4levels in HCV infected patients treated with direct‐acting antiviral drugs. • Furthermore, clinicians must recommend sofosbuvir, ribavirin, and daclatasvir instead of sofosbuvir, peg‐IFN‐a, and ribavirin for genotype 1 to avoid this increasing risk of hypothyroidism.
Article
Autoimmune thyroid diseases (AITD) are chronic thyroiditis triggered by autoimmune reactions. They can lead to a progressive destruction of glandular tissue that may cause either an increase or a decrease of thyroid hormones. AITD span from hyperthyroidism of Graves’ disease to hypothyroidism of Hashimoto’s thyroiditis, encompassing subtitle subclinical thyroid dysfunctions, too. Quite recently AITD have been named among organ specific autoimmune disorders. Firstly, AITD pathological findings were reported in the 19th century mainly by Hashimoto, Graves, Stokes, Basedow and Parry. However, only in the 20th century did Ehrlich’s assays pave the way for the pathogenesis of all autoimmune disorders. At present a unique etiology has not been associated with AITD. Environmental factors as well as genetic susceptibility have been considered most frequently involved in the onset of thyroid autoimmunity. AITD diagnosis still remains a difficult and complex issue. This is because morphological and serological reports are not always interchangeable since they record different degrees of glandular destruction. Furthermore, the trend of serum data is not always appropriate with the clinical course of AITD patients. Lastly, AITD therapy is symptomatic and not yet completely adequate. By an historical excursus on AITD diagnostic methods this assay summarizes old and new pivotal features setting the AITD diagnosis. Specially, to comment the developments on AIDT diagnostic methods achieved to date, AIDT serological data and histological characters are analyzed. KEY WORDS: Autoimmune thyroiditis; Hashimoto disease; Graves disease
Article
Introduction: Autoimmune thyroid diseases are reported in no treated hepatitis C virus (HCV) infection. The standard interferon alpha (IFNα) treatment is associated with an increase of thyroid damage and dysfunction. The present cohort prospective study compared thyroid function and autoimmunity in HCV patients' monoinfected and coinfected HCV-HIV at baseline, during and after IFNα therapy. Methods: We studied 790 HCV infected patients: G1 (monoinfected HCV: N=580) and G2 (HCV-HIV coinfected: N=210). They were evaluated for thyroid function and thyroid tiroperoxidase antibodies (TPOAb) at baseline and 235 patients (G1: 183; G2: 52) post IFNα therapy. If thyroid dysfunction (TD) was diagnosed, they were reevaluated at 12 month after discontinuation to determine whether the TD was transitory or definitive. Results: No difference was found in the prevalence of TD at baseline in G1 (7.6%) and G2 (9%). However, monoinfected patients showed a higher prevalence of TPOAb positivity with a women preponderance in this group. There was no difference in TD between both groups during IFNα therapy (G1 23.5% vs G2 19.2%). In G1 the autoimmune TD was higher than in G2 (67.4% vs 30%, p=0.02). Autoimmune TD during IFNα tended to evolve to definitive hypothyroidism and non-autoimmune TD recovered euthyroidism after IFNα discontinuation. The presence of positive TPOAb (RR 3.55) and female gender (RR 2.4) were associated with the development of TD with IFNα therapy. Conclusion: Our hypothesis is the importance of HCV in G1 and G2, combined with IFNα in triggering TD and TPOAb positivity, not described in other diseases' applications.
Article
Background Dysregulation of the type 1 interferon (IFN)‐related signaling pathway predisposes one to autoimmune diseases. Possible associations of single‐nucleotide polymorphisms (SNPs) of Secreted phosphoprotein 1 (SPP1) and B lymphocyte kinase (BLK) of the type 1 IFN‐related signaling pathway with autoimmune thyroid disease (AITD) in an ethnic Chinese (i.e., Taiwanese) population were tested. Methods Totally, 83 Hashimoto's thyroiditis (HT) patients, 319 Graves’ disease (GD) patients, and 369 controls were enrolled. Genotypes of the two SNPs (rs1126772 and rs1126616) of SPP1 and two SNPs (rs13277113 and rs2736340) of BLK were determined. Results Our results showed reduced percentages of the G allele of rs13277113 of BLK in GD (p=0.037, odds ratio (OR)=0.78, 95% confidence interval (CI)=0.62~0.99) and HT (p=0.002, OR=0.54, 95% CI=0.36~0.81), compared to the controls. At the same time, lower frequencies of the C allele of rs2736340 of BLK in GD (p=0.025, OR=0.76, 95% CI=0.60~0.97) and HT (p=0.003, OR=0.53, 95% CI=0.35~0.81) than the controls were also observed. There were significantly higher AT haplotype frequencies of rs1327713 and rs2736340 in GD and HT patients than in the controls (p=0.025, OR=1.31, 95% CI=1.03~1.67, and p=0.003, OR=1.89, 95% CI=1.24~2.87, respectively). Moreover, the anti‐microsomal antibody titer was associated with rs2736340. Conclusions Genetic variants of rs13277113 and rs2736340 of BLK were associated with susceptibility to GD, HT, and AITD in an ethnic Chinese population. Our results suggest the BLK may participate in the pathogenesis of GD, HT, and AITD. This article is protected by copyright. All rights reserved.
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Concurrent presentation of acute hepatitis A virus (HAV) infection and Graves' disease has not been reported in literature worldwide. Although there is no well-established mechanism that explains the induction of Graves' disease by HAV to date, our case suggests that HAV infection may be responsible for inducing Graves' disease. A healthy 27-year-old female presented fever, palpitation, and diarrhea, and she was subsequently diagnosed as acute HAV infection. Concurrently, she showed hyperthyroidism, and the diagnosis was made as Graves' disease. She had never had symptoms that suggested hyperthyroidism, and previous thyroid function test was normal. Acute HAV infection was recovered by conservative management, however, thyroid dysfunction was maintained even after normalization of liver enzymes. Methimazole was used to treat Graves' disease. We report a case of concurrent acute HAV infection and Graves' disease in a patient without preexisting thyroid disease. This suggests that HAV infection may be a trigger for an autoimmune thyroid disease in susceptible individuals.
Article
Aim Patients with chronic hepatitis C are frequently treated with interferon (IFN)-α. Autoimmune thyroid disease occurs in 20% ~ 40% of IFN-α-treated patients. In this study, the effects of IFN-α administration on triggering and regulating autoimmune thyroiditis in various animal models were evaluated. Main methods Exogenous IFN-α was given to naive CBA mice, and both thyroglobulin (TG) immunization-induced (CBA) and spontaneous autoimmune thyroiditis (NOD·H-2 h4) models. Thyroid function, and anti-thyroglobulin antibody (ATA) and B-cell-activating factor (BAFF) levels were measured. Alterations in transcriptome profiles were analyzed. Key findings In the TG-induced thyroiditis model, IFN-α administration reduced plasma free thyroxine levels but did not alter ATA titers, BAFF levels, or the severity of histological changes. Interestingly, even without changes in thyroid functions, four of eight mice in the IFN-α alone group exhibited thyroiditis compared to the control group. Immunologically, mice in the IFN-α group exhibited profound CD3⁺ cell infiltration in the thyroid and higher plasma BAFF levels compared to the control group. Meanwhile, pathological and serological alterations after IFN-α administration were not observed in the NOD·H-2 h4 model. An RNA sequencing analysis revealed that immunoregulatory signatures were not excited by IFN-α treatment in naive CBA mice. Meanwhile, innate and adaptive immunity, inflammatory cytokine, chemokine, and cell-killing signaling pathways were all stimulated by IFN-α administration after TG immunization of CBA mice. Significance We confirmed the remarkable effects of IFN-α in both initiating thyroid immunity and modulating thyroid function and immunoregulatory signatures in established autoimmune thyroiditis. We suggest that IFN-α should be administered with caution in clinical settings.
Article
Background and aims: Although chronic hepatitis C virus (HCV) infection affects millions of people in India, few studies have assessed host, viral, and disease characteristics of chronically infected patients at national and regional levels. Such information is critical to support large scale screening and treatment initiatives for chronic HCV infection in India. Methods: Patients with known chronic HCV infection making routine or for-cause visits to the participating study centers were enrolled in this observational study. Patients attended a single outpatient visit during which demographics and medical history were collected, a physical examination was performed, and blood and urine samples were collected for laboratory assessments. Samples were analyzed to determine HCV genotypes and subtypes, and genotypes of interferon lambda 3 (IFNL3) single nucleotide polymorphism. No therapeutic interventions were administered. Results: We enrolled 500 patients at 19 centers, categorized into four geographic regions (North, South, East, and West). All patients self-identified as Indian, and most (66 %) were male. Genotype 3 was the most common genotype overall (54 %); however, its prevalence varied greatly by region, ranging from 34 % in the South to 69 % in the East. Genotypes 1 (24 %) and 4 (6 %) were the next most common, and HCV genotype could not be determined for 16 % of patients. Conclusions: This prospective survey suggests that demographics, viral, and host factors in patients with chronic HCV infection are highly variable in India and pose significant challenges for the implementation of broad-scale screening and treatment initiatives.
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Hepatitis C virus (HCV) has become an increasingly concerning global disease. While it is well known to causes a chronic hepatitis that can be largely asymptomatic until the development of cirrhosis and/or hepatocellular carcinoma (HCC), chronic HCV can also lead to extrahepatic manifestations (EHMs) which can contribute to further morbidity and mortality. This chapter will discuss the pathophysiology and data supporting the causal relationship between chronic HCV infection and its EHMs as well as address the influence of HCV treatment on these disorders, particularly in the age of direct-acting antiviral agents.
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This study was conducted to investigate body mass index (BMI), levels of cholesterol and triglycerides in prison inmates at the Institution for Reform and Rehabilitation in Southern Libya to be considered as an indication about their health and the provided foods. The results of this study showed that 26.5% of BMI of the prison inmates were found to be higher than the normal levels. Generally, the average level of cholesterol and triglycerides concentrations were found to be within normal range 142.6 mg/dl and 135.4 mg/dl, respectively. The findings also established that there were a significant relationship and direct correlation between BMI levels and age and concentration of cholesterol and triglycerides levels. The results of this showed that the served foods for these prison inmates are well balanced as indicated by their cholesterol and triglycerides levels.
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The IFITM family of proteins have recently been identified as important host effector molecules of the type I interferon response against viruses. IFITM1 has been identified as a potent antiviral effector against HCV, while the related family members IFITM2 and IFITM3 have been described to have antiviral effects against a broad range of RNA viruses. Here, we demonstrate that IFITM2 and IFITM3 play an integral role in the interferon response against HCV and act at the level of late entry stages of HCV infection. We have established that in hepatocytes, IFITM2 and IFITM3 localise to the late and early endosomes respectively, as well as the lysosome. Furthermore, we have demonstrated that S-palmitoylation of all three IFITM proteins is essential for anti-HCV activity, whilst the conserved tyrosine residue in the NTD of IFITM2 and IFITM3 plays a significant role in protein localisation. However, this tyrosine was found to be dispensable for anti-HCV activity, with mutation of the tyrosine resulting in an IFITM1-like phenotype with the retention of anti-HCV activity and co-localisation of IFITM2 and IFITM3 with CD81. In conclusion, we propose that the IFITM proteins act in a coordinated manner to restrict HCV infection by targeting the endocytosed HCV virion for lysosomal degradation and demonstrate that the actions of the IFITM proteins are indeed virus and cell-type specific.
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HCV chronic infection is characterized by possible development of both hepatic and extrahepatic manifestations. The infection by this both hepatotropic and lymphotropic virus is responsible for polyoligoclonal B-lymphocyte expansion, leading to several immune-mediated disorders. Mixed cryoglobulinemia syndrome that in some cases may evolve to frank B-cell non-Hodgkin's lymphoma is the prototype of HCV-driven autoimmune and lymphoproliferative disorders. The HCV oncogenic potential has been suggested by several clinicoepidemiological and laboratory studies; it includes hepatocellular carcinoma, B-cell non-Hodgkin's lymphoma and papillary thyroid cancer. The definition HCV syndrome refers to the complex of HCV-driven diseases; these latter are characterized by heterogeneous geographical distribution, suggesting a role of other important genetic and/or environmental cofactors. The natural history of HCV syndrome is the result of a multifactorial and multistep pathogenetic process, which may evolve from mild manifestations to systemic autoimmune disorders, and less frequently to malignant neoplasias. The present updated review analyzes the clinical and pathogenetic aspects of the main HCV-associated diseases.
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Background: Males have excess advanced liver disease and cirrhosis risk including from chronic hepatitis C virus (HCV) infection though the reasons are unclear. Goal: To examine the role variants in genes involved in androgen and estrogen biosynthesis and metabolism play in HCV-related liver disease risk in males. Methods: We performed a cross-sectional study evaluating single nucleotide polymorphisms (SNPs) in 16 candidate genes involved in androgen and estrogen ligand and receptor synthesis and risk of advanced hepatic fibrosis (F3/F4-F4) and inflammation (A2/A3-A3). We calculated adjusted odds ratios (ORs) using logistic regression and used multifactor dimensionality reduction (MDR) analysis to assess for gene-environment interaction. Results: Among 466 chronically HCV-infected males, 59% (n = 274) had advanced fibrosis and 54% (n = 252) had advanced inflammation. Nine of 472 SNPs were significantly associated with fibrosis risk; 4 in AKR1C3 (e.g., AKR1C3 rs2186174: ORadj = 2.04, 95% CI 1.38-3.02), 1 each in AKR1C2 and ESR1, and 1 in HSD17B6. Four SNPs were associated with inflammation risk, 2 in SRD5A1 (e.g., SRD5A1 rs248800: ORadj = 1.86, 95% CI 1.20-2.88) and 1 each in AKR1C2 and AKR1C3. MDR analysis identified a single AKR1C3 locus (rs2186174) as the best model for advanced fibrosis; while a 4-locus model with diabetes, AKR1C2 rs12414884, SRD5A1 rs6555406, and SRD5A1 rs248800 was best for inflammation. Conclusions: The consistency of our findings suggests AKR1C isoenzymes 2 and 3, and potentially SRD5A1, may play a role in progression of HCV-related liver disease in males. Future studies are needed to validate these findings and to assess if similar associations exist in females.
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Aim: The aim of the present study was to examine the changes in the expression of T-cell activation markers, namely CD4+ CD25+ and CD8+ in patients with AITD, namely Graves’ disease and Hashimoto's thyroiditis as well as colloid nodular goitre. HLA-DR, LFA-3, and peripheral total lymphocytic count are also measured. Materials and Methods: We compared the expression of CD4, CD25, and CD8 surface markers in peripheral blood lymphocyte in Graves’ disease and Hashimoto's thyroiditis as autoimmune thyroid diseases, as well as colloid goitre in comparison with healthy controls. Also, LFA-3 and HLA-DR were measured in the same groups using three-color flow cytometry. Total lymphocytic count in peripheral blood, thyroid function tests, antithyroid antibodies were also included in the laboratory investigations. The total number of participants was 65. All were recruited from endocrine clinics in a tertiary care hospital in the southern region of Saudi Arabia. All participants underwent history taking, clinical examination, laboratory workup, and radiological investigations. Neck ultrasound, technecium pertechnetateψψ thyroid uptake, and fine-needle aspiration and cytology (FNAC) of the thyroid were done when indicated. The study was approved by the Hospital Research Isthics Committee and informed consents were obtained from all participants before enrollment in the study. Results: In comparison with thecontrol group, activation markers CD4, CD25, and CD8 were lower in the autoimmune thyroid diseases. Lymphocyte function antigen-3 (CD58) and total lymphocytic count were higher in the AIT diseases whereas HLA-DR was lower than that in the control group. The CD4/CD8 ratio was lower in the AITD compared with the healthy euthyroid subjects. No difference was found between patients with colloid nodular goitre and the healthy control in any of the study variables except for LFA-3 which was significantly higher in the colloid goitre group. Conclusion: Our findings indicate downregulation of CD4+ CD25+ Treg as well as CD8+ T cells in autoimmune thyroid diseases. Downregulation of suppressor T lymphocytes helps initiation, progression, and maintenance of the autoimmune thyroid diseases. Lower HLA-DR and higher CD58 in AITDs indicate their role in the expression of the autoantigen and its escape from the immune surveillance. High levels of LFA-3 in colloid goitre indicate that the autoimmune process needs interacting factors, and not only the high level of LFA-3.
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Background: The interferon-free regimen of ABT-450 with ritonavir (ABT-450/r), ombitasvir, and dasabuvir with or without ribavirin has shown efficacy in inducing a sustained virologic response in a phase 2 study involving patients with hepatitis C virus (HCV) genotype 1 infection. We conducted two phase 3 trials to examine the efficacy and safety of this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. Methods: We randomly assigned 419 patients with HCV genotype 1b infection (PEARL-III study) and 305 patients with genotype 1a infection (PEARL-IV study) to 12 weeks of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), dasabuvir (250 mg twice daily), and ribavirin administered according to body weight or to matching placebo for ribavirin. The primary efficacy end point was a sustained virologic response (an HCV RNA level of <25 IU per milliliter) 12 weeks after the end of treatment. Results: The study regimen resulted in high rates of sustained virologic response among patients with HCV genotype 1b infection (99.5% with ribavirin and 99.0% without ribavirin) and among those with genotype 1a infection (97.0% and 90.2%, respectively). Of patients with genotype 1b infection, 1 had virologic failure, and 2 did not have data available at post-treatment week 12. Among patients with genotype 1a infection, the rate of virologic failure was higher in the ribavirin-free group than in the ribavirin group (7.8% vs. 2.0%). In both studies, decreases in the hemoglobin level were significantly more common in patients receiving ribavirin. Two patients (0.3%) discontinued the study drugs owing to adverse events. The most common adverse events were fatigue, headache, and nausea. Conclusions: Twelve weeks of treatment with ABT-450/r-ombitasvir and dasabuvir without ribavirin was associated with high rates of sustained virologic response among previously untreated patients with HCV genotype 1 infection. Rates of virologic failure were higher without ribavirin than with ribavirin among patients with genotype 1a infection but not among those with genotype 1b infection. (Funded by AbbVie; PEARL-III and PEARL-IV ClinicalTrials.gov numbers, NCT01767116 and NCT01833533.).
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Background: The interferon-free combination of the protease inhibitor ABT-450 with ritonavir (ABT-450/r) and the NS5A inhibitor ombitasvir (also known as ABT-267) plus the nonnucleoside polymerase inhibitor dasabuvir (also known as ABT-333) and ribavirin has shown efficacy against the hepatitis C virus (HCV) in patients with HCV genotype 1 infection. In this phase 3 trial, we evaluated this regimen in previously untreated patients with HCV genotype 1 infection and no cirrhosis. Methods: In this multicenter, randomized, double-blind, placebo-controlled trial, we assigned previously untreated patients with HCV genotype 1 infection, in a 3:1 ratio, to an active regimen consisting of a single-tablet coformulation of ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir), and dasabuvir (250 mg twice daily) with ribavirin (in doses determined according to body weight) (group A) or matching placebos (group B). The patients received the study treatment during a 12-week double-blind period. The primary end point was sustained virologic response at 12 weeks after the end of treatment. The primary analysis compared the response rate in group A with the response rate (78%) in a historical control group of previously untreated patients without cirrhosis who received telaprevir with peginterferon and ribavirin. Adverse events occurring during the double-blind period were compared between group A and group B. Results: A total of 631 patients received at least one dose of the study drugs. The rate of sustained virologic response in group A was 96.2% (95% confidence interval, 94.5 to 97.9), which was superior to the historical control rate. Virologic failure during treatment and relapse after treatment occurred in 0.2% and 1.5%, respectively, of the patients in group A. The response rates in group A were 95.3% among patients with HCV genotype 1a infection and 98.0% among those with HCV genotype 1b infection. The rate of discontinuation due to adverse events was 0.6% in each study group. Nausea, pruritus, insomnia, diarrhea, and asthenia occurred in significantly more patients in group A than in group B (P<0.05 for all comparisons). Reductions in the hemoglobin level were all of grade 1 or 2; reductions of grade 1 and 2 occurred in 47.5% and 5.8%, respectively, of the patients in group A, whereas grade 1 reductions occurred in 2.5% of the patients in group B. Conclusions: In previously untreated patients with HCV genotype 1 infection and no cirrhosis, a 12-week multitargeted regimen of ABT-450/r-ombitasvir and dasabuvir with ribavirin was highly effective and was associated with a low rate of treatment discontinuation. (Funded by AbbVie; SAPPHIRE-I ClinicalTrials.gov number, NCT01716585.).
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Background: In this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon-ribavirin. Methods: We enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon-ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r-ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon-ribavirin. Results: A total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively. Conclusions: Rates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.).
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The autoimmune thyroid diseases (AITD) are complex diseases that are caused by an interaction between susceptibility genes and environmental triggers. Genetic susceptibility, in combination with external factors (e.g., dietary iodine), is believed to initiate the autoimmune response to thyroid antigens. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Various techniques have been used to identify the genes contributing to the etiology of AITD, including candidate gene analysis and whole genome screening. These studies have enabled the identification of several loci (genetic regions) that are linked with AITD, and in some of these loci putative AITD susceptibility genes have been identified. Some of these genes/loci are unique to Graves' disease (GD) and Hashimoto's thyroiditis (HT), and some are common to both diseases, indicating that there is a shared genetic susceptibility to GD and HT. The putative GD and HT susceptibility genes include both immune modifying genes (e.g., human leukocyte antigen, cytotoxic T lymphocyte antigen-4) and thyroid-specific genes (e.g., TSH receptor, thyroglobulin). Most likely these loci interact, and their interactions may influence disease phenotype and severity. It is hoped that in the near future additional AITD susceptibility genes will be identified and the mechanisms by which they induce AITD will be unraveled.
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Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (-1623A→G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (-1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5' TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon α, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFNα) and genetic (TG) factors to trigger AITD.
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In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon-ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon-ribavirin for 8 weeks and placebo with peginterferon-ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon-ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon-ribavirin for 12 weeks, followed by 36 weeks of peginterferon-ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon-ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Telaprevir with peginterferon-ribavirin, as compared with peginterferon-ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.).
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Autoimmunity and viral infections are closely associated fields, and viruses have been proposed as a likely aetiological, contributory or triggering factors of systemic autoimmune diseases. Hepatitis C virus seems to be the virus usually associated with the appearance of autoimmune diseases, and the relationship between chronic hepatitis C virus infection and some autoimmune disease has been studied. For some of these disorders their association with hepatitis C virus infection is well recognized while for others it remains probable or weak. Examples of autoimmune phenomena observed in chronic hepatitis C virus infection include rheumatoid arthritis, thyroid disease, cryoglobulinaemia, immune thrombocytopenic purpura, systemic lupus erythematosus and sjogren syndrome. To date, the etiological role and the pathogenetic involvement of the hepatitis C infection remains unknown.The aim of this study is to assess the presence of different autoimmune manifestations of hepatitis C virus infection reported in literature.
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CD4(+) T cells are commonly divided into regulatory T (Treg) cells and conventional T helper (Th) cells. Th cells control adaptive immunity against pathogens and cancer by activating other effector immune cells. Treg cells are defined as CD4(+) T cells in charge of suppressing potentially deleterious activities of Th cells. This review briefly summarizes the current knowledge in the Treg field and defines some key questions that remain to be answered. Suggested functions for Treg cells include: prevention of autoimmune diseases by maintaining self-tolerance; suppression of allergy, asthma and pathogen-induced immunopathology; feto-maternal tolerance; and oral tolerance. Identification of Treg cells remains problematic, because accumulating evidence suggests that all the presently-used Treg markers (CD25, CTLA-4, GITR, LAG-3, CD127 and Foxp3) represent general T-cell activation markers, rather than being truly Treg-specific. Treg-cell activation is antigen-specific, which implies that suppressive activities of Treg cells are antigen-dependent. It has been proposed that Treg cells would be self-reactive, but extensive TCR repertoire analysis suggests that self-reactivity may be the exception rather than the rule. The classification of Treg cells as a separate lineage remains controversial because the ability to suppress is not an exclusive Treg property. Suppressive activities attributed to Treg cells may in reality, at least in some experimental settings, be exerted by conventional Th cell subsets, such as Th1, Th2, Th17 and T follicular (Tfh) cells. Recent reports have also demonstrated that Foxp3(+) Treg cells may differentiate in vivo into conventional effector Th cells, with or without concomitant downregulation of Foxp3.
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Hashimoto's thyroiditis (HT) is one of the autoimmune disorders of the thyroid gland. The pathogenesis of HT has not been clearly understood. This study was designed to investigate plasma transforming growth factor-beta1 (TGF-beta1), vascular endothelial growth factor (VEGF), and nitrate/nitrite (NOx - two end products of nitric oxide [NO] metabolism) in HT. Forty patients diagnosed HT and 40 age- and sex-matched healthy controls were included in the study. TGF-beta1 and VEGF levels were measured by ELISA, NOx levels were measured spectrophotometrically. Plasma TGF-beta1 and VEGF were decreased, and NOx increased in HT patients in comparison with controls. There was a significant correlation between TGF-beta1 and VEGF, and weak but significant correlation between TGF-beta1 and NOx in HT. This study indicates that TGF-beta1, VEGF and NO probably have a role in the pathogenesis of Hashimoto's thyroiditis, and development of autoimmunity. Clearly, further studies are necessary to establish the exact mechanism of TGF-beta1, VEGF and NO interaction in Hashimoto's thyroiditis.
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A large gene region, called GD-1, was first described by this laboratory as linked to Graves' disease (GD) and included the gene for the thyroid-stimulating hormone receptor (TSHR). Recent studies have now suggested an association of TSHR intronic polymorphisms with GD. We have taken the opportunity to examine a population of well-characterized patients with autoimmune thyroid disease (AITD) typed for an additional thyroid susceptibility gene, the immunoregulatory gene for cytotoxic T-lymphocyte antigen 4 (CTLA-4), to examine its relationship with the susceptibility to GD endowed by TSHR gene polymorphisms. We used TSHR-SNP-rs2268458, located in intron 1 of the TSHR gene, measured using standard PCR-RFLP procedures, as our marker for the TSHR gene association. We genotyped 200 patients with GD, 83 patients with Hashimoto's thyroiditis (HT), and 118 healthy controls (all female Caucasians). The allele and genotype frequencies from GD patients, but not HT patients, were significantly different from controls. The frequency of the combined genotype (allele) CC + TC was significantly higher in GD patients versus controls, suggesting that the C-containing genotype increased the risk for GD in a dominant manner (p = 0.018, odds ratio [OR] = 1.8). When compared with CTLA-4 (A/G)(49) single-nucleotide polymorphism (SNP), we were unable to demonstrate additive risk in patients with established AITD. Further, subsetting the patients (n = 120) into those with clinically significant Graves' ophthalmopathy (GO) showed no association with the TSHR SNP. These results demonstrated that the intronic TSHR-SNP-rs2268458 was associated with GD, but not with HT, thus indicating that the TSHR gene has the potential to increase susceptibility to GD. However, we were not able to demonstrate any additive risk with the CTLA-4 (A/G)(49) SNP, which is, therefore, an independent risk factor for AITD. This suggested that, within the limits of the study population, each of these two genes provided a small contribution to GD susceptibility and that neither was essential. In addition, there was no evidence for the TSHR gene association adding to the risk of developing GO. Direct functional analyses are now needed to help explain the mechanisms of this TSHR gene susceptibility to GD.
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We investigated human leukocyte antigen (HLA) class I and class II antigens in 56 Japanese patients with subacute thyroiditis (SAT) who visited our out-patient clinic between 1988 and 1990. We found SAT to be associated with not only HLA-B35 (40 patients; P < 0.000001; relative risk, 18.02), but also with HLA-B67 antigens (9 patients; P < 0.00001; relative risk, 11.20). No heterozygotes of HLA-B35 or HLA-B67 were found in any of the 56 patients with SAT. Either HLA-B35 or HLA-B67 antigen is found in 87% of patients with SAT. When season of onset and clinical course of SAT were compared in the 49 patients with HLA-B35-positive SAT (B35-SAT) and HLA-B67-positive SAT (B67-SAT), we were able to identify certain characteristics: 1) B67-SAT often followed the course from transient thyrotoxicosis to a hypothyroid phase to a euthyroid phase [6 of 9 B67-SAT (67%) vs. 10 of 40 B35-SAT (25%); P < 0.05]; and 2) B67-SAT occurred mostly during the summer or autumn and at a higher rate than did B35-SAR [8 of 9 B67-SAT (89%) vs. 17 of 40 B35-SAT (43%)], whereas B35-SAT occurred throughout the year. We conclude that there are at least two types of SAT that can be classified by association with either HLA-B35 or HLA-B67 antigens.
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Regulatory T (Treg) cells play an important role in the pathogenesis of autoimmune thyroid disorders (AITD). New subsets of CD4(+)CD69(+) and CD4(+)NKG2D(+) T lymphocytes that behave as regulatory cells have been recently reported. The role of these immunoregulatory lymphocytes has not been previously explored in AITD. We analyzed by multi-parametric flow cytometry different Treg cell subsets in peripheral blood from 32 patients with AITD and 19 controls, and in thyroid tissue from seven patients. The suppressive activity was measured by an assay of inhibition of lymphocyte activation. We found a significant increased percentage of CD4(+)CD69(+)IL-10(+), CD4(+)CD69(+)NKG2D(+), and CD4(+)CD69(+)IL-10(+)NKG2D(+) cells, in peripheral blood from GD patients compared to controls. The increase in CD4(+)CD69(+)IL-10(+) and CD4(+)CD69(+)IL-10(+)NKG2D(+) T cells was especially remarkable in patients with active Graves' ophthalmopathy (GO), and a significant positive correlation between GO activity and CD4(+)CD69(+)IL-10(+) or CD4(+)CD69(+)IL-10(+)NKG2D(+) cells was also found. In addition, these cells were increased in patients with a more severe and/or prolonged disease. Thyroid from AITD patients showed an increased proportion of CD69(+) regulatory T cells subpopulations compared to autologous peripheral blood. The presence of CD69(+), NKG2D(+), and IL-10(+) cells was confirmed by immunofluorescence microscopy. In vitro functional assays showed that CD69(+) Treg cells exerted an important suppressive effect on the activation of T effector cells in controls, but not in AITD patients. Our findings suggest that the levels of CD69(+) regulatory lymphocytes are increased in AITD patients, but they are apparently unable to down-modulate the autoimmune response and tissue damage.
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Hepatitis C virus (HCV) is a potent human pathogen and is one of the main causes of chronic hepatitis round the world. The present review describes the evidence-based consensus on the diagnosis, prevention and management of HCV disease. Various techniques, for the detection of anti-HCV immunoglobulin G immunoassays, detection of HCV RNA by identifying virus-specific molecules nucleic acid testings, recognition of core antigen for diagnosis of HCV, quantitative antigen assay, have been used to detect HCV RNA and core antigen. Advanced technologies such as nanoparticle-based diagnostic assays, loop-mediated isothermal amplification and aptamers and Ortho trak-C assay have also come to the front that provides best detection results with greater ease and specificity for detection of HCV. It is of immense importance to prevent this infection especially among the sexual partners, injecting drug users, mother-to-infant transmission of HCV, household contact, healthcare workers and people who get tattoos and piercing on their skin. Management of this infection is intended to eradicate it out of the body of patients. Management includes examining the treatment (efficacy and protection), assessment of hepatic condition before commencing therapy, controlling the parameters upon which dual and triple therapies work, monitoring the body after treatment and adjusting the co-factors. Examining the treatment in some special groups of people (HIV/HCV co-infected, hemodialysis patients, renal transplanted patients).
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Despite recent discoveries of genetic variants associated with autoimmunity and infection, genetic control of the human immune system during homeostasis is poorly understood. We undertook a comprehensive immunophenotyping approach, analyzing 78,000 immune traits in 669 female twins. From the top 151 heritable traits (up to 96% heritable), we used replicated GWAS to obtain 297 SNP associations at 11 genetic loci, explaining up to 36% of the variation of 19 traits. We found multiple associations with canonical traits of all major immune cell subsets and uncovered insights into genetic control for regulatory T cells. This data set also revealed traits associated with loci known to confer autoimmune susceptibility, providing mechanistic hypotheses linking immune traits with the etiology of disease. Our data establish a bioresource that links genetic control elements associated with normal immune traits to common autoimmune and infectious diseases, providing a shortcut to identifying potential mechanisms of immune-related diseases. Copyright © 2015 Elsevier Inc. All rights reserved.
Article
Hepatitis C virus (HCV) infection is a major health problem worldwide. The effects of chronic infection include cirrhosis, end-stage liver disease, and hepatocellular carcinoma. As a result of shared routes of transmission, co-infection with HIV is a substantial problem, and individuals infected with both viruses have poorer outcomes than do peers infected with one virus. No effective vaccine exists, although persistent HCV infection is potentially curable. The standard of care has been subcutaneous interferon alfa and oral ribavirin for 24-72 weeks. This treatment results in a sustained virological response in around 50% of individuals, and is complicated by clinically significant adverse events. In the past 10 years, advances in HCV cell culture have enabled an improved understanding of HCV virology, which has led to development of many new direct-acting antiviral drugs that target key components of virus replication. These direct-acting drugs allow for simplified and shortened treatments for HCV that can be given as oral regimens with increased tolerability and efficacy than interferon and ribavirin. Remaining obstacles include access to appropriate care and treatment, and development of a vaccine. Copyright © 2015 Elsevier Ltd. All rights reserved.
Article
After encountering antigen, helper T (TH) cells undergo differentiation to effector cells, which can secrete high levels of interferon-, interleukin-4 (IL-4), IL-10 and other immunomodulators. How TH cells acquire, and remember, new patterns of gene expression is an area of intensive investigation. The process is remarkably plastic, with cytokines being key regulators. Extrinsic signals seem to be integrated into cell-intrinsic programming, in what is becoming an intriguing story of regulated development. We summarize the latest insights into mechanisms that govern the lineage choices that are made during TH-cell responses to foreign pathogens.
Article
Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic-epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.
Article
Recent advances in our understanding of genetic-epigenetic interactions have unraveled new mechanisms underlying the etiology of complex autoimmune diseases. Autoimmune thyroid diseases (AITDs) are highly prevalent, affecting 1% to 5% of the population. The major AITDs include Graves disease (GD) and Hashimoto's thyroiditis (HT); although these diseases contrast clinically, their pathogenesis involves shared immunogenetic mechanisms. Genetic data point to the involvement of both shared and unique genes. Among the shared susceptibility genes, HLA-DRβ1-Arg74 (human leukocyte antigen DR containing an arginine at position β74) confers the strongest risk. Recent genome-wide analyses have revealed new putative candidate genes. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with AITD susceptibility genes. Dissecting the genetic-epigenetic interactions underlying the pathogenesis of AITD is essential to uncover new therapeutic targets.
Article
A higher prevalence of immunological processes has recently been reported in patients with hepatitis C virus (HCV) infection, focusing the attention of physicians and researchers on the close association between HCV and immune disorders. HCV lymphotropism represents the most important step in the pathogenesis of virus-related immunological diseases and experimental, virologic, and clinical evidence has demonstrated a trigger role for HCV both in systemic autoimmune diseases, such as rheumatoid arthritis, Sjögren syndrome, hemolytic anemia and severe thrombocytopenia, and in organ-specific autoimmune diseases, such as autoimmune hepatitis, thyroid disorders and diabetes. This review will outline the principal aspects of such HCV-induced immunological alterations, focusing on the prevalence of these less characterized HCV extrahepatic manifestations.
Article
Hashimoto's thyroiditis (HT) has long been epidemiologically associated with excess iodine levels. However, the underlying immunological mechanisms still remain largely unexplored. Th17 cells are commonly recognized as playing vital roles in various autoimmune diseases. Here we show that intra-thyroid infiltrating Th17 cells and serum IL-17 levels were significantly increased in HT patients. However, the concentration of serum IL-17 was inversely correlated with patients' residual thyroid function while the heterogeneously expressed thyroid IL-17 was directly correlated with local fibrosis. Administration of moderate high levels of iodine was found to facilitate the polarization of murine splenic naïve T cells into Th17 cells, whereas extreme high levels of iodine favored Th1 polarization and inhibited Treg development. These findings suggest that both Th1 and Th17 cells may be involved in the pathogenesis of HT and high levels of iodine may play a critical role in this process by modulating T cell differentiation.
Article
Thyroid autoimmunity involves loss of tolerance to thyroid proteins in genetically susceptible individuals in association with environmental factors. In central-tolerance, intrathymic autoantigen presentation deletes immature T-cells with high affinity for autoantigen-derived peptides. Regulatory T-cells provide an alternative mechanism to silence autoimmune T-cells in the periphery. The thyrotropin-receptor (TSHR), thyroid peroxidase (TPO) and thyroglobulin (Tg) have unusual properties ("immunogenicity") that contribute to breaking tolerance including size, abundance, membrane-association, glycosylation and polymorphisms. Insight into loss of tolerance to thyroid proteins comes from spontaneous and induced animal models:- 1) Intrathymic expression controls self-tolerance to the TSHR, not TPO or Tg; 2) Regulatory T-cells are not involved in TSHR self-tolerance and instead control the balance between Graves' disease and thyroiditis; 3) Breaking TSHR-tolerance involves contributions from MHC molecules (humans and induced mouse models), TSHR polymorphism(s) (humans) and alternative splicing (mice); 4) Loss of tolerance to Tg before TPO indicates that greater Tg immunogenicity versus TPO dominates central tolerance expectations; 5) Tolerance is induced by thyroid autoantigen administration before autoimmunity is established; 6) Interferon-α therapy for hepatitis C infection enhances thyroid autoimmunity in patients with intact immunity; Graves' disease developing after T cell depletion reflects reconstitution autoimmunity; 7) Most environmental factors (including excess iodine) "reveal", but do not induce thyroid autoimmunity. Micro-organisms likely exert their effects via bystander stimulation. Finally, no single mechanism explains the loss of tolerance to thyroid proteins. The goal of inducing self-tolerance to prevent autoimmune thyroid disease will require accurate prediction of at-risk individuals together with an antigen-specific, not blanket, therapeutic approach.
Article
To clarify changes in the intrathyroidal natural killer T (NKT) cell subset, which prevents autoimmunity in patients with Graves' disease (GD), we examined intrathyroidal and peripheral lymphocytes in 11 patients with GD and peripheral lymphocytes in nine healthy volunteers using three-color flow cytometry. The proportion of CD161(+) T cell receptor V alpha 24(+)V beta 11(+) cells, which represent the NKT cell subset, was lower in the thyroid of patients with GD than in the peripheral blood of the same patients and in the peripheral blood of healthy subjects. These results indicate that the proportion of intrathyroidal NKT cells is decreased in patients with GD and that this decrease may contribute to incomplete regulation of autoreactive T cells in GD.
Article
We examined peripheral lymphocyte subsets in patients with autoimmune thyroid disease, or subacute thyroiditis, in the active stage when possible. During destructive thyrotoxicosis arising from aggravation of Hashimoto's thyroiditis, both the numbers and proportions of αβ T cell receptor (TCR) negative T (WT31− CD3+) cells and CD8 (CD4− CD8+) cells decreased and those of CD4+ CD8+ cells increased slightly, resulting in proportional increases in CD4 (CD4+ CD8−) cells. non-T, non-B (CD5− CD19−) cells, and the CD4/CD8 cell ratio. Changes were similar in active subacute thyroiditis. During stimulative thyrotoxicosis in active Graves' disease, the numbers of such T lymphocyte subsets were not changed, but only the number of CD5+ B (CD5+CD19+) cells increased markedly, resulting in proportional decreases in total T (CD3+) cells, αβ+ TCR T (WT31+ CD3+) cells, CD8 cells, and non-T, non-B cells. A serial study of some of the patients showed opposite changes in αβ TCR− T cells, the CD4/CD8 cell ratio, and CD5+ B cells between the active stages of Graves' and Hashimoto's diseases. αβ TCR− T cells were mostly γδ TCR+ T (IIF2+ CD3+) cells in these patients. These data suggest that αβ TCR T (γδTCR+ T), CD8, and CD4+ CD8+ cells are important in thyroid destruction in Hashimoto's disease and subacute thyroiditis, and that CD5+ B cells arc important in thyroid stimulation in Graves' disease.
Article
The autoimmune thyroid diseases (AITDs) include two related disorders, Craves disease (CD) and Hashimoto thyroiditis, in which perturbations of immune regulation result in an immune attack on the thyroid gland. The AITDs are multifactorial and develop in genetically susceptible individuals. However, the genes responsible for this susceptibility remain unknown. Recently, we initiated a whole-genome linkage study of patients with AITD, in order to identify their susceptibility genes. We studied a data set of 53 multiplex, multigenerational AITD families (323 individuals), using highly polymorphic and densely spaced microsatellite markers (intermarker distance <10 cM). Linkage analysis was performed by use of two-point and multipoint parametric methods (classic LOD-score analysis). While studying chromosome 20, we found a locus on chromosome 20q11.2 that was strongly linked to GD. A maximum two-point LOD score of 3.2 was obtained at marker D20S195, assuming a recessive mode of inheritance and a penetrance of .3. The maximum nonparametric LOD score was 2.4 (P = .00043); this score also was obtained at marker D20S195. Multipoint linkage analysis yielded a maximum LOD score of 3.5 for a 6-cM interval between markers D20S195 and D20S107. There was no evidence for heterogeneity in our sample. In our view, these results indicate strong evidence for linkage and suggest the presence of a major CD-susceptibility gene on chromosome 20q11.2.
Article
Les relations entre infection par le virus de l'hépatite C (VHC) et maladies thyroïdiennes soulèvent plusieurs questions: la prévalence de l'auto-immunité thyroïdienne chez les patients atteints d'hépatite chronique C, la prévalence de l'infection par le VHC chez les patients atteints de maladies thyroïdiennes auto-immunes, les effets sur la fonction thyroïdienne du traitement par interféron alpha conduit pour hépatite chronique C. L'objectif de ce travail est de préciser, à travers une revue de la littérature, ces différents aspects tant sur le plan physiopathologique, que sur le plan de la conduite diagnostique et thérapeutique.
Article
Background: Autoimmune thyroid disease (AITD) pathogenesis may result from a loss of immune tolerance to thyroid antigens. Regulatory T cells (Tregs) control immune responses, prevent excessive inflammation, and may be dysfunctional in AITD. We investigated the role of Tregs in Hashimoto's thyroiditis (HT) and Graves' disease (GD), complicated by Down syndrome (DS). Our goal was to identify differences in CD4(+)CD25(high) Treg function or number in patients with GD and HT, compared to healthy controls (HC). Methods: Treg number was assessed by flow cytometric analysis in samples from 20 AITD patients (seven GD, 13 HT), nine HC, and seven individuals with DS, a genetic disorder associated with multiple autoimmune disorders including AITD. Treg function was assessed by the inhibition of proliferation (radioactive thymidine incorporation into DNA) of blood-derived T effector (Teff) cells by Tregs in a coculture. Various methods of stimulation were contrasted. Cytokine levels were determined in conditioned media from the co-cultures. Results: No differences were found in the frequency of Tregs as a percentage of CD4(+) cells between AITD and HC. AITD Tregs were less capable of inhibiting the proliferation of Teff cells when compared to HC; however, the impairment was dependent on the type of stimulation used. DS patients without AITD exhibited normal Treg function. We observed few differences in cytokine production between HC and AITD patients. Conclusions: Tregs from AITD patients are partly dysfunctional, possibly explaining their autoimmunity. Future work will elucidate the diagnostic potential and pathophysiology of Tregs in AITD.
Article
Association between autoimmune thyroid diseases (AITD) and hepatitis C is controversial, but may occur or worsen during alpha-interferon treatment. The mechanism responsible for autoimmune diseases in infected patients has not been fully elucidated. This study aims to evaluate the frequency of AITD in chronic hepatitis C and the association of CXCL10 and AITD. One hundred and three patients with chronic hepatitis C and 96 controls were prospectively selected to clinical, hormonal, thyroid autoimmunity and ultrasound exams, besides thyroxine-binding globulin (TBG) and CXCL10 measurements and hepatic biopsies. The frequency of AITD among infected subjects was similar to controls. TT3 and TT4 distributions were right shifted, as was TBG, which correlated to both of them. Thyroid heterogeneity and hypoechogenicity were associated with AITD. Increased vascularization was more prevalent in chronic hepatitis C.CXCL10 was higher in infected patients (p=0.007) but was not related to thyroid dysfunction. Increase in CXCL10 levels were consistent with hepatic necroinflammatory activity (p=0.011). In summary, no association was found between chronic hepatitis C and AITD. Infected subjects had higher TT3 and TT4 which were correlated to TBG. Increased CXCL10 was not associated to thyroid dysfunction in HCV-infected population.
Article
Background: Autoimmune and non-autoimmune thyroiditis frequently occur in persons with hepatitis C virus (HCV) infection. Treatment with interferon alpha (IFNα) is also associated with significant risk for the development of thyroiditis. To explore HCV-thyroid interactions at a cellular level, we evaluated whether a human thyroid cell line (ML1) could be infected productively with HCV in vitro. Methods and results: ML1 cells showed robust surface expression of the major HCV receptor CD81. Using a highly sensitive, strand-specific reverse transcription polymerase chain reaction assay, positive-sense and negative-sense HCV RNA were detected in ML1 cell lysates at days 3, 7, and 14 postinfection with HCV. HCV core protein was expressed at high levels in ML1 supernatants at days 1, 3, 5, 7, and 14 postinfection. The nonstructural protein NS5A was also detected in ML1 cell lysates by Western blotting. HCV entry into ML1 cells was shown to be dependent on the HCV entry factors CD81 and SR-B1/CLA1, while IFNα inhibited HCV replication in ML1 cells in a dose-dependent manner. Supernatants from HCV-infected ML1 cells were able to infect fresh ML1 cells productively, suggesting that infectious virions could be transferred from infected to naïve thyroid cells in vivo. Additionally, HCV infection of ML1 cells led to increased expression of the pro-inflammatory cytokine IL-8. Conclusions: For the first time, we have demonstrated that HCV can infect human thyroid cells in vitro. These findings strongly suggest that HCV infection of thyrocytes may play a role in the association between chronic HCV infection and thyroid autoimmunity. Furthermore, the thyroid may serve as an extrahepatic reservoir for HCV viral replication, thus contributing to the persistence of viral infection and to the development of thyroid autoimmunity.
Article
We have investigated whether lipopolysaccharide (LPS) induces substance P (SP) and somatostatin (SOM) in popliteal lymph nodes in vivo and whether macrophages are a source of SP and SOM in vitro. We have also investigated the effect of SP and SOM treatment on the production of cytokines. SP reached a maximum 3 days after injection of LPS (100 μg/footpad) and then declined. SOM expression after LPS injection reached a maximum at 5–7 days. Stimulation of thioglycolate-elicited peritoneal macrophages with LPS (20 μg/ml), recombinant interferon-=γ (rIFN-=γ, 100 U/ml), and LPS plus rIFN-=γ induced SOM and SP. Thioglycolate-elicited, unstimulated peritoneal macrophages also synthesized these peptides. SOM (10–12–10–8M) significantly inhibited IL-6 and IFN-=γ production, whereas SP at those concentrations enhanced cytokine production by activated lymphocytes and macrophages. These findings suggest that neuropeptides which originate from macrophages and nerve fibers act as immunomodulators to mediate changes in the pattern of cytokine production.
Article
To clarify controversies on the prevalence and clinical significance of thyroid autoimmunity in hepatitis C virus (HCV) infection. A prospective controlled and follow-up study. Serum thyroid microsomal antibody (TMA) and thyroid stimulating hormone were assayed and compared in a consecutive, unselected series of 130 patients with chronic HCV infection, 130 sex/age (± 2 years)-matched patients with chronic hepatitis B virus (HBV) infection and 260 matched normal controls. The prevalence of thyroid autoantibodies in male patients with chronic HCV was < 2%. The prevalence of TMA (< 1 : 400) in female patients with chronic HCV infection was significantly higher than that of HBV controls (22.1 vs. 1.6%; P < 0.001), and higher but not significant compared with normal controls (13.5%). However, the trend of increasing prevalence with age in normal controls was not observed in HCV patients. TMA seropositive female HCV patients were not different from seronegative counterparts in age, duration of infection, HLA haplotype, associated autoantibodies and liver histology but had a significantly higher prevalence of genotype 1b/2b mixed infection (P < 0.01) and anti-GOR (P < 0.05). Of the 23 HCV patients seropositive for thyroid autoantibodies, seven had Hashimoto's thyroiditis, two had Graves' disease and three had received subtotal thyroidectomy. During follow-up, four of 15 female patients showed a 14–16-fold increase in TMA titre and one developed hyperthyroidism. Patients with thyroid autoantibodies did not show a propensity to develop thyroid dysfunction during interferon therapy. These results suggest a weak association between HCV and thyroid autoimmunity in females. As in the ordinary population with thyroid autoantibodies, they should be evaluated for thyroid status and be followed-up if thyroid autoimmunity is evident. However, seropositivity of thyroid autoantibodies is not a contraindication to interferon therapy.
Article
Interferon and ribavirin combination therapy for chronic hepatitis C produces a number of well-described side effects that are dominated by fatigue, influenza-like symptoms, hematologic abnormalities, and neuropsychiatric symptoms. Combination therapy with pegylated interferons (peginterferon alfa-2a and alfa-2b) yields an adverse event profile similar to standard interferon, although the frequency of certain adverse events may vary by preparation. Premature withdrawal from therapy due to adverse events was required in 10% to 14% of participants in registration trials of these agents. Most adverse events were safely and effectively managed by dose reduction using predetermined criteria. The most common indications for dose reduction were hematologic abnormalities, such as anemia and neutropenia, with the latter more frequent in peginterferon treatment arms. Recent data suggest that maintaining adherence to a prescribed treatment regimen can enhance antiviral response. Strategies to maximize adherence are being developed and, in the future, may include early identification of and therapy for depression and the selective use of hematopoietic growth factors to ameliorate hematologic abnormalities.
Article
Hepatitis C virus (HCV) infection affects 2-3% of the population, approximately 170 million people worldwide, causing chronic HCV-related hepatitis with subsequent liver cirrhosis, hepatic failure, hepatocellular cancer, and liver-related mortality in a large number of patients. The gold standard therapy, pegylated interferon alpha in combination with ribavirin can eradicate hepatitis C virus infection in approx. 40% of treatment-naïve patients infected with HCV genotype G1, and only 15-20% of patients with previous treatment. Success rate is substantially improved with the development and registration of two direct acting anti-hepatitis C virus protease inhibitors (boceprevir and telaprevir) in the second decade of 21st century: combined with the standard therapy, almost three quarter of previously untreated, and more than half of previously unsuccessfully treated patients can achieve sustained viral response with protease inhibitor based triple therapies. A major barrier to successful treatment is the association of peginterferon/ribavirin therapy with frequent and sometimes serious adverse effects. In clinical trials, approximately 10-15% of treated patients discontinue peginterferon and ribavirin due to adverse events; however, in routine clinical practice, the rate of treatment discontinuation has been reported to be substantially higher. The side effects of peginterferon/ribavirin therapy affect virtually all organ systems, and addition of protease inhibitor can amplify these side effects (particularly anemia), and/or may lead to new ones (i.e., dysgeusia with boceprevir or skin rush with telaprevir). There is considerable regional and global variability in the nature and prevalence of these adverse effects as well as in the best strategies to ameliorate their impact on hepatitis C virus treatment. This article summarizes the side effects of dual and triple therapies and their management based on the labels of the drugs, on a comprehensive literature review, as well as on the recently published opinion of an international panel of experts - with the provision of providing help for the physicians treating hepatitis C virus infection to achieve the best possible success with the highest possible safety for the patients.
Article
Unlabelled: Males have strikingly increased risk of advanced liver disease. However, the association between testosterone and risk of hepatitis C virus (HCV)-related advanced liver disease is unknown. We performed a cross-sectional study in male veterans with chronic HCV. Blood samples were obtained to measure total serum testosterone and perform the FibroSURE-ActiTest. Other risk-factor data were obtained through systematic questionnaires (e.g., alcohol), physical measurements (e.g., body mass index), and serological tests (e.g., viral load). The association between total testosterone and risk of advanced hepatic fibrosis (F3 and F3/F4) and inflammatory activity (A3 and A2/3) measured by the FibroSURE-ActiTest was evaluated with logistic regression. A total of 308 eligible study participants were prospectively recruited (mean age: 57; 52% African-American). There were 105 cases with advanced fibrosis and 203 mild fibrosis controls as well as 88 cases with advanced inflammatory activity and 220 mild activity controls. Mean total serum testosterone was significantly higher in advanced fibrosis cases as well as advanced inflammatory activity cases, compared to mild disease controls (6.0 versus 5.3 ng/mL and 5.9 versus 5.4 ng/mL, respectively). We observed a significant 25% increase in advanced fibrosis risk and 15% increase in advanced inflammatory activity risk for each 1-ng/mL increase in total serum testosterone. Total testosterone in the upper tertile was associated with an even greater excess risk of advanced fibrosis than advanced inflammatory activity (odds ratio [OR](adjusted advanced fibrosis) = 3.74; 95% CI: 1.86-6.54 versus OR(adjusted advanced inflammatory activity) = 2.23; 95% CI: 1.07-4.93, respectively). Conclusions: Total serum testosterone is associated with an increased risk of both advanced hepatic fibrosis and advanced hepatic inflammatory activity in HCV-infected men. Testosterone may be important in the pathogenesis of HCV-related advanced liver disease in males.
Article
Eight children with Graves' disease and five children with Hashimoto's thyroiditis admitted to the Pediatric Department of the University of Trieste in the period 1980 to 1985 have been reviewed. The purpose of this study was to define the clinical course of autoimmune thyroid diseases and to evaluate the frequency of HLA haplotypes and immunological abnormalities in the affected patients and in their family members. Antithyroid microsomal antibodies were observed in 87.5% of the hyperthyroid patients and in 13.3% of their siblings and parents, in all the patients affected by Hashimoto's thyroiditis and in 18.18% of their first degree relatives. HLA A1-B8 was found to be associated with Graves' disease, HLA B35 was linked to chronic lymphocytic thyroiditis. Using monoclonal antibodies for enumeration of the subsets of T lymphocytes a deficit in suppressor T-cells was demonstrated in subjects affected by autoimmune thyroid diseases as in other immunological disorders.
Article
A sexual dysmorphism in the immune response has been described and females display an increased incidence of autoimmune diseases. Experimental data show that sex steroids influence immune cell development and have immunomodulatory effects. The distribution, the action (genomic and nongenomic), the sex and tissue-depending expression pattern of estrogen, progesterone and androgen receptors and their functional disruptions in corresponding receptor knockout animals will be discussed, pointing out the difference among sex steroid hormones. Recent advances indicate an immunomodulatory role of sex steroids in the pathogenesis of systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. The outcomes of the clinical trials will help to find the best use of sex steroids in combination with current therapeutic drugs in autoimmune diseases. Sex steroid receptor modulating drugs will provide new therapeutic approaches in these pathologies.
Article
An HLA-DR variant containing Arginine at position 74 of the DRbeta1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases (AITD), Graves' disease (GD) and Hashimoto's thyroiditis (HT), while Glutamine at position DRbeta1-74 is protective. We hypothesized that the DRbeta1-Arg74 variant is able to present pathogenic thyroglobulin (Tg) peptides to T-cells more efficiently, thereby triggering thyroid autoimmunity. Indeed, we have previously identified 4 human Tg (hTg) peptides that bind specifically to DRbeta1-Arg74 with much weaker binding to the protective variant DRbeta1-Gln74. The aim of our study was to examine in vivo whether an hTg peptide that binds strongly and specifically to DRbeta1-Arg74 is capable of stimulating T-cells during the induction of thyroiditis in a "humanized" mouse expressing human DR3, and in patients positive for Tg antibodies. Sequencing of exon 2 of the DR transgene in the DR3 mice, null for endogenous MHC II molecules, confirmed that they expressed the disease-associated DRbeta1-Arg74 variant, thus making them an ideal in vivo model to test the presentation of hTg peptides by DRbeta1-Arg74 HLA-DR. Induction of EAT in the DR3 mice lead to T-cell stimulation and proliferation to Tg.2098, a strong and specific DRbeta1-Arg74 binder, while a non-binding control peptide, Tg.2766 did not induce this response. Moreover, Tg.2098 stimulated T-cells from 4 individuals who were positive for thyroglobulin antibodies, demonstrating that Tg.2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in EAT and AITD. Energetic analysis of the complex formed by Tg.2098 and DRbeta-Arg74 has shown that the origin of the affinity was determined by residues 1, 7 and 9 in the peptide, while the selectivity of the peptide for the MHC was determined by the Asp in position 4. The disease-protective substitution R74Q, leads to reduction in affinity due to changes in local interaction with D4 as well as non-local interaction with other residues. The electrostatic potential on the surface of the DRbeta-Arg74-Tg.2098 complex has a unique signature which may be recognized by T-cell receptors leading to autoimmune thyroiditis. Taken together these findings suggest that Tg.2098, a strong and specific binder to the disease-associated HLA-DRbeta-Arg74, is a major human T-cell epitope and participant in the pathoetiology of AITD.
Article
To assess the histologic prevalence of immune-mediated thyroid, pituitary, and adrenal diseases in postmortem cases with hepatitis C. We reviewed 108 consecutive cases of chronic hepatitis C in patients in whom a complete postmortem examination was performed. All microscopic and histologic slides of the thyroid, pituitary, and adrenal reports were reviewed and assessed for evidence of autoimmune diseases. These were compared with a control group of 100 postmortem cases without hepatitis C. In chronic hepatitis C infection, there is a heightened immune response resulting in many autoimmune diseases. The commonest endocrinopathy in association with this chronic infection is thyroid disease, a finding confirmed in our current study. Among the 108 postmortem cases of hepatitis C, there were 14 cases (13%) with evidence of thyroiditis. No cases of pituitary or adrenal disease were found. The mean age of the patients was 52 years (range, 29 to 68). This frequency compared with 7 cases of thyroid disease (7%) in the control group (no significant difference between the 2 groups). On the basis of our postmortem data, thyroid disease was the only major endocrinopathy associated with hepatitis C infection, with a prevalence of 13%. This was comparable with other serologic and nonhistologic antemortem findings. There was no evidence of pituitary or adrenal involvement.