Thyroid disturbance related to hepatitis C therapy Danilovic DLS et al. this hypothesis. Previous studies have suggested that TT3 and TT4 levels increase in cases of chronic liver disease in proportion to the severity of the liver dysfunction (due to high TBG levels).15,16 We confirmed the existence of two main forms of IIT (autoimmune and non-autoimmune). The mechanisms involved in autoimmune thyroiditis associated with IFNa have not yet been clarified. IFNa and its receptor activate the JAK-STAT pathway, activating the expression of genes encoding cytokines and adhesion molecules. IFNa also increases the expression of MHC class I antigens, activates cytotoxic T cells, and induces the T helper 1-mediated immune response.6 The mean time to the diagnosis of IFNa- induced autoimmune thyroid disturbance was six months, which suggests that longer exposure is required to stimulate immune mechanisms. The direct effects of IFNa on the thyroid may be responsible for non-autoimmune thyroiditis.6 It is possible that HCV itself promotes a local immune response in thyrocytes. In addition, IFNa directly induces thyrocyte death and inhibits TSH-induced gene expression and protein production of Tg, TPO and the sodium iodine symporter,17,18 which promote follicular destruction and hypothyroidism. We found a significant increase in thyr- oglobulin levels within three months of the onset of therapy in the cases of destructive thyroiditis, indicating the direct, acute and destructive effects of IFNa on follicular cells. One limitation of this study is the small number of patients, especially those who developed IIT. Nevertheless, we were able to identify an association between the female gender and autoimmune IIT, as previously reported in larger popula- tions.19,20 Our data support the conclusion that the develop- ment of IIT is not related to the type of IFNa (i.e., conventional vs. pegylated).21 We are the first to describe an association between reduced pre-treatment levels of TT3 and TT4 and slightly increased TSH levels as predictors of non-autoimmune IIT. We speculate that a smaller thyroid hormone reserve facilitated the hormonal disturbance after a direct cellular lesion caused by IFNa. The higher frequency (8%) of destructive thyroiditis (compared to previous data)7,22 is remarkable. This dis- crepancy may have occurred because of the early hormonal evaluation that we performed (at three months). CDUS would help to differentiate thyrotoxicosis caused by either destructive thyroiditis or auto-immune thyroiditis (Graves’ disease). Unfortunately, Graves’ disease was not diagnosed during the IFNa therapy. Our patients with destructive thyroiditis had either mild (pattern II) or marked (pattern III) increases in vascularization. In contrast to amiodarone- induced thyroiditis, we expected that destructive thyroiditis would lead to CDUS patterns of less than II, and autoimmune thyroiditis would lead to pattern III.8 Possible explanations for these findings are the use of delayed CDUS exams for diagnosis and the concomitant autoimmune mechanisms that were induced, which were represented by dramatic increases in anti-Tg and anti-TPO antibody levels (case 2). Both of the patients developed rapid thyroid volume shrinkage, which is compatible with destructive lesions. Additional CDUS exams are necessary to define the role of ultrasound in differentiating IFNa- induced thyrotoxicosis. In summary, treating HCV infections with IFNa and ribavirin induces autoimmune and non-autoimmune thyr- oiditis and hormonal changes, which are represented by 1762 CLINICS 2011;66(10):1757-1763 decreases in TT3 and TT4 levels despite stable levels of FT4 and TSH. Consequently, a thyroid hormonal evaluation, including measurements of FT4, TSH, and antithyroid antibody levels, should be mandatory before therapy. As thyroid disturbances were detected within three months of treatment, we suggest an early hormonal re-evaluation during IFNa treatment. Thus, thyroid disturbances will not remain undiagnosed. ACKNOWLEDGEMENTS This study received financial support from Funda¸ca˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo (FAPESP) grant 2006/06080-2. REFERENCES 1. Antonelli A, Ferri C, Fallahi P, Ferrari SM, Ghinoi A, Rotondi M, et al. Thyroid disorders in chronic hepatitis C virus infection. Thyroid. 2006;16:563-72, doi: 10.1089/thy.2006.16.563. 2. 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