Thyroid disturbance related to hepatitis C therapy Danilovic DLS et al. IFNa has several adverse effects, ranging from influenza- like symptoms to severe hematologic abnormalities and pulmonary complications.4 These adverse effects provoke dose reduction in up to 40% of cases and treatment withdrawal in up to 14% of cases.5 IFNa can commonly induce thyroiditis, which is classified as either autoimmune or non-autoimmune interferon- induced thyroiditis (IIT).6 Autoimmune IIT manifests as Hashimoto’s thyroiditis, which is defined by an emerge of or worse in antithyroid antibody levels with or without hypothyroidism. In rare cases, autoimmune IIT also mani- fests as Graves’ disease, which is defined by antithyroid antibodies with hyperthyroidism. Non-autoimmune IIT presents as destructive thyroiditis and hypothyroidism.6 Hashimoto’s thyroiditis is diagnosed in up to 40% of patients, and hypothyroidism can be triggered by IFNa.7 Hypothyroidism frequently escapes diagnosis due to the overlap of its symptoms with those induced by IFNa itself, such as fatigue, somnolence and depression. Rarely, IFNa induces Graves’ disease, the diagnosis of which is based on hyperthyroidism with goiter and the presence of thyroid stimulating hormone receptor antibo- dies.7 Its treatment demands precaution due to the hepato- toxic and hematologic side effects of antithyroid drugs. Destructive thyroiditis represents a form of non-auto- immune IIT characterized by self-limited thyrotoxicosis with a triphasic evolution similar to that of subacute thyroiditis. In the first phase, the patient shows thyrotox- icosis, low radioiodine uptake and the absence of antithyr- oid antibodies. Hypothyroidism follows euthyroidism within a few weeks to months. Hypothyroidism can persist, especially in the presence of antithyroid antibodies. Destructive thyroiditis may recur upon re-treatment, and it is not necessary to discontinue IFNa use.6 Our study prospectively characterized the manifestations of thyroid disturbances induced by IFNa and ribavirin therapy in chronically HCV-infected subjects. MATERIALS AND METHODS Patients Out of the 112 subjects diagnosed with chronic hepatitis C and receiving follow-up at the Hospital das Cl´ınicas da Faculdade de Medicina da Universidade de Sa˜o Paulo between January 2007 and July 2009, 26 patients who were beginning IFNa and ribavirin therapy were prospectively selected. None of the patients had previously been treated with interferon. The diagnosis of chronic HCV infection was based on a positive anti-HCV serology and the presence of viral nucleic acid, as evaluated by polymerase chain reaction (PCR) using the commercial Amplicor HCV test (Roche Diagnostics Systems). The type and duration of the IFNa therapy was based on the viral genotype. Non- cirrhotic genotypes 2 and 3 received non-pegylated IFNa for 24 weeks. Cirrhotic genotypes 2 and 3, genotype 1 and HCV with human immunodeficiency virus (HIV) co- infection (independent of the HCV genotype) received pegylated IFNa for 48 weeks, provided that the HCV RNA became undetectable or that the number of viral copies decreased at least 2 logs (100-fold) within 12 weeks. Any patients with HBV infections, those who were pregnant, and those who were using amiodarone or lithium were excluded. 1758 CLINICS 2011;66(10):1757-1763 The study was approved by the institutional research ethics committee, and all of the subjects gave their informed written consent to participate. Methods The patients underwent clinical and hormonal evalua- tions before treatment and every 12 weeks during treatment. Serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured using conventional methods. HCV genotyping was performed using a reverse hybridization assay, the Line Probe Assay (INNO-LiPA HCV/ VERSANTTM HCV Genotype Assay, Bayer Corporation, Tarrytown, NY, USA). Total T3 (TT3), total T4 (TT4), free T4 (FT4), TSH and thyroglobulin (Tg) levels were measured using commercial fluoroimmunoassay kits (AutoDELFIAH, Upsala, Turku, Finland). Serum anti-thyroglobulin (anti-Tg) and anti-thyro- peroxidase (anti-TPO) antibodies were measured using commercial indirect fluoroimmunoassay kits (AutoDELFIAH, Upsala, Turku, Finland). Thyroid-stimulating hormone recep- tor antibody (TRAb) levels were evaluated by an immunor- adiometric assay (RSR, Cardiff, Wales, UK). Hashimoto’s thyroiditis was defined by increased levels of anti-Tg or anti-TPO antibodies (.35 mUI/L). Subclinical hypothyroidism was diagnosed when TSH levels were increased (.4.5 mUI/L) and when FT4 levels were within the normal range (0.7 – 1.5 ng/dL), whereas overt hypothyroidism was diagnosed based on increased TSH levels associated with decreased FT4 levels. Thyrotoxicosis was characterized by increased FT4 levels and depressed TSH levels (,0.03 mUI/L). Destructive thyroiditis was diagnosed by the presence of thyrotoxicosis in the absence of TRAbs, followed by subclinical or overt hypothyroidism (either transitory or permanent). Color-flow Doppler thyroid ultrasonography (CDUS) was performed by a single investigator (7.5–12 MHz, Philips HDI 5000 device; Philips Medical Systems, Bothell, WA, USA) before therapy and after 12 months of therapy. The thyroid parenchyma and echogenicity, the presence of nodules, the glandular volume and vascularization were evaluated. Vascularization was classified according to Bogazzi et al., as follows: pattern 0, the absence of intraparenchymal vascularity or minimal spots; pattern I, the presence of parenchymal blood flow with a patchy and uneven distribution; pattern II, a mild increase in color-flow Doppler signal with patchy distribution; pattern III, a marked increase in color-flow Doppler signal with diffuse homogeneous distribution.8 Statistical analysis The data were processed using SPSS 13.0 software. Two- tailed p-values were calculated, and p-values of ,0.05 were considered to be statistically significant. The categorical variables are presented as absolute and relative frequencies (percentages). Any differences were evaluated by Pearson’s x2 test and Fisher’s exact test, where appropriate. The continuous variables are presented as the means ¡ standard deviations. Kolmogorov-Smirnov or Shapiro-Wilk statistics were used to test for any deviations from normality. Any differences among the studied subgroups were determined using Student’s t-test and one-way ANOVA for the normally distributed data, and the Mann-Whitney U, Wilcoxon, and Kruskal-Wallis tests were used for the non-normally distributed data.