Interferon induced Autoimmune Thyroid Disease (AITD): a model for human autoimmunity
Introduction
Interferons are a class of cytokines possessing antiviral and antitumoral activity. Interferons are grouped into Types I and II. Type I interferons are acid-stable and include alpha, beta and omega subtypes. All Type I interferons are coded by genes on chromosome 9. Interferon genes require an activator to induce expression. One of these activators is known to be viruses [1]. The antiviral activity of interferons has led to the use of synthetic forms to control viral infections such as hepatitis C.
IFN-α treatment for many conditions has been associated with AITD. The first study to report this association was performed in 1986 by Oberg and colleagues [2], who studied patients receiving interferon for carcinoid tumors. The association is most recognized in hepatitis C but has been noted to occur in a variety of other conditions as well [3], [4], [5]. In this review, we will review studies linking interferon treatment and thyroid autoimmunity.
Section snippets
AITD in hepatitis C: is there an association?
Before discussing the association between interferon and AITD, it is important to recognize that hepatitis C has been claimed to be associated with thyroid disorders, even in the absence of interferon treatment (Table 1). In two studies of patients with hepatitis C virus who had not received interferon therapy, the incidence of thyroid dysfunction and antibody positivity was significantly higher than in the control population [3], [6]. Another study of 66 patients with hepatitis C who were not
Interferon and AITD in hepatitis C
The link between interferon and thyroid autoimmunity was most commonly studied in hepatitis C patients (Table 2). Carella et al. [10] found that 38.8% of patients receiving interferon for 12 months for hepatitis C developed de novo TAb's while 5.3% developed thyroid dysfunction. One patient developed thyroid dysfunction and three patients developed positive TAb's 6 months after interferon therapy was terminated, suggesting that thyroid monitoring should be continued even beyond treatment
Interferon and AITD in other diseases
Interferon therapy has also been noted to cause AITD in malignancies such as breast cancer, carcinoid and hematologic malignancies (Table 3) [18], [19], [20], [21], [22]. Leukocyte-derived interferon was used as treatment until recombinant interferon became available. Fentiman et al. [19] found that 50% of women treated with interferon as adjuvant therapy for breast cancer developed positive TAb's and 30% developed AITD. All patients who developed AITD had positive TAb's before or during
Thyroid disorders associated with interferon therapy
IFN-α has been associated with development of both Hashimoto's disease and Graves' disease, as well as subacute thyroiditis. In a review of 13 studies [10], [11], [12], [13], [15], [21], [22], [24], [25], [26], [27], [28], [29] totaling over 1800 patients treated with interferon for various types of hepatitis and malignancies, 114 patients developed thyroid dysfunction [30]. Of those who developed thyroid dysfunction, 62% developed hypothyroidism and 38% hyperthyroidism [30]. Additionally, IFN
Predisposition to interferon-induced thyroid autoimmunity
Possible factors predisposing to interferon-induced AITD include factors related to the underlying condition, the dose and duration of interferon treatment, and risk factors for AITD in general. As previously mentioned, there is no clear-cut indication that certain conditions predispose to interferon induced AITD, even though some investigators have claimed that hepatitis C by itself may predispose patients to AITD [3], [4], [5], [6]. The dose and duration of interferon treatment have also been
Possible mechanisms of interferon-induced thyroid autoimmunity
The mechanisms by which interferon induces thyroid autoimmunity are unclear. One proposed mechanism is MHC class I antigen upregulation and subsequent antibody development [5]. Evidence suggests that interferon upregulates MHC class I antigen expression in the thyroid thereby inducing autoantibody formation [5]. Another possibility is a direct effect of IFN on the thyroid. This hypothesis is supported by data showing IFN induced thyroid dysfunction without TAb's in up to 10% of IFN-treated
Acknowledgements
This work was supported in part by grants DK61659 & DK58072 from NIDDKD (to YT).
Take-home messages
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Interferon (IFN) α treatment for various conditions, mostly for hepatitis C infection, is associated with development of thyroid autoimmunity.
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Risk factors for development of IFN-induced autoimmune thyroid disease (AITD) include dose and duration of IFN-α treatment, female gender, the presence of thyroid autoantibodies (Tab's), and possibly genetic factors such as human leukocyte antigen (HLA).
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It is
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These authors contributed equally to the work presented in this manuscript.