CLINICS 2011;66(10):1757-1763 RESULTS Clinical features A total of 26 patients, including 15 female patients, were treated with IFNa and ribavirin. The mean patient age was 43.1¡11.8 years. Of the subjects, 85% had normal thyroid function and no antithyroid antibodies before the onset of treatment. Four patients (15%) were diagnosed with Hashimoto’s thyroiditis with euthyroidism. Throughout the duration of the IFNa treatment, 14 patients maintained normal thyroid function. IFNa induced thyroiditis in 35% of the cases. Autoimmune thyroiditis, which is characterized as an emerge of antithyroidal antibodies and overt autoimmune hypothyroidism, was detected in 19% of the cases (two patients). Destructive thyroiditis occurred in 8% of the patients, and 8% developed non-autoimmune subclinical hypothyroidism. IIT appeared after 6.2¡3.3 months of therapy. However, all of the cases of destructive thyroiditis involved asymptomatic thyrotoxico- sis, with hormonal diagnosis occurring as early as three months into the treatment. Finally, 11% of the patients remained in a state of euthyroidism after hepatitis C therapy despite the prior presence of antithyroidal antibodies. Patients with normal thyroid function during IFNa treatment In the 14 patients (eight males) with normal thyroid function before and during the IFNa treatment, a significant decrease in TT3 levels (p = 0.038) was observed after 12 months of therapy, along with a significant reduction in TT4 levels after 3 and 12 months (p = 0.039 and p = 0.008, respectively), despite TT3 and TT4 levels falling within the normal range. Interestingly, the FT4 and TSH levels remained stable. A decrease in ALT levels (p = 0.055), suggestive of the precocious regression of hepatocellular lesions, was also noted, although the AST levels presented no significant decrease (Figure 1). Patients with interferon-induced thyroiditis The clinical, hormonal and CDUS characteristics of the subjects with autoimmune and non-autoimmune IIT were compared to those of patients with no therapy-related thyroid disorders (Table 1). All of the patients who were diagnosed with autoimmune IIT were female, which represented a significantly higher number of females (p = 0.045) compared to subjects with no therapy-related thyroid disorders. The pre-treatment levels of TT3 (141¡18 ng/dL, p = 0.018) and TT4 (8.8¡0.7 mg/dL, p = 0.005) were significantly lower, and the TSH levels tended to be higher (3.1¡1.2 mUI/L, p = 0.079) in the patients with non-autoimmune IIT compared to the patients with no thyroid disorders (TT3, 184¡36 ng/L; TT4, 11.9¡2.0 mg/dL; TSH, 1.8¡0.7 mUI/L). No differences in age, race, HIV co-infections, the HCV genotype, the type of IFNa used (pegylated or non-pegylated), the length of the therapy and the CDUS features were observed between the IIT patients and the subjects with no thyroid-related disorders. Two subjects developed autoimmune hypothyroidism during the IFNa treatment. One had prior anti-Tg and anti- TPO antibodies, and the other had developed both antibodies at the onset of the hormonal disturbance. No specific symptoms were reported, even with TSH levels as high as 123 mU/L and 128 mU/L, respectively. 1759 Thyroid disturbance related to hepatitis C therapy Danilovic DLS et al. Levothyroxine replacement therapy was necessary and was maintained through the final evaluation. The thyroid disturbances in the cases of autoimmune IIT were unre- solved during follow-up. The hormonal dysfunction in both of the cases of non- autoimmune subclinical hypothyroidism regressed during or after IFNa withdrawal. One of the cases presented an asymptomatic TSH increase (5.8 mU/L) within five months of the IFNa therapy, with subsequent normalization despite the maintenance of the antiviral therapy. The other case showed an asymptomatic TSH increase (6.2 mU/L) after ten months of therapy, and hormonal normalization occurred six months after IFNa withdrawal. Two patients had destructive IFNa-induced thyroiditis IFNa (Figure 2). The first case presented as asymptomatic thyrotoxicosis within three months of therapy (Figure 2A). The thyroglobulin levels rose from 27.7 ng/dL to 106 ng/dL. The tests for the anti-Tg and anti-TPO antibodies and TRAb remained negative. The initial CDUS revealed heterogeneous isoechoic parenchyma and increased vascularization (pattern III), and the glandular volume was 8.4 g. One month after the diagnosis of thyrotoxicosis, a new examination revealed a decrease in thyroid vascularization (pattern II) and concomi- tant glandular shrinkage (42%). Such modifications persisted during CDUS performed 8.5 months after the end of the therapy. The second case had a similar evolution (Figure 2B). The diagnosis of asymptomatic thyrotoxicosis was made within 3.4 months of the onset of therapy. The thyroglobulin levels rose from 10.5 ng/dL to 147 ng/dL. Although negative for TRAb, anti-Tg and anti-TPO antibodies were detected at low levels (41 UI/L and 66 UI/L, respectively). The initial CDUS revealed a heterogeneous isoechoic parenchyma and mildly increased vascularization (pattern II), and the gland- ular volume was 18 g. Three months after the diagnosis of thyrotoxicosis, another examination revealed a hypoechoic parenchyma with increased vascularization (pattern III) and a 14.4% decrease in thyroid volume, which persisted according to CDUS performed two months after the end of therapy. DISCUSSION We performed a careful prospective study of 26 HCV- infected patients during IFNa and ribavirin treatment, and only 54% of these patients maintained normal thyroid function, which should alert the clinician to these important potential side effects. Previous data identified a decrease in FT4 levels within reference values concomitant to a slight reduction in free T3 levels without TSH or thyroglobulin changes during six months of conventional IFNa therapy.9 We observed decreases in both TT3 and TT4 levels within 12 months of therapy with conventional and pegylated IFNa in associa- tion with ribavirin. As FT4 and TSH remained stable, we could not attribute such hormonal changes to an IFNa-induced organification defect.10 The decreases in TT3 and TT4 levels may be related to interleukin-6 (IL-6). Previous studies have reported an increase in IL-6 serum levels with conventional and pegylated IFNa treatments.11,12 IL-6 reduces thyroperoxidase mRNA levels and TSH-stimulated thyroid hormone secretion separately from decreasing thyroid hormone binding pro- teins.13 Therefore, IL-6 reduces TT3 without changes in FT4 or TSH levels. Corssmit et al. reported the acute effects of IFNa in healthy volunteers.14 They observed significant