Changes in thyroid-stimulating hormone and thyroxine during hepatitis C virus infection and after direct-acting antiviral therapy independent of interferon exposure: a prospective paired cohort study

Thyroid dysfunction is a recognized extrahepatic manifestation of hepatitis C virus (HCV) infection, historically described in the context of interferon therapy or autoimmune thyroid disease. In the era of direct-acting antiviral (DAA) therapy, the clinical significance of subtle thyroid hormone alterations during untreated infection remains unclear, particularly given potential implications for routine screening, early detection of subclinical dysfunction, and long-term metabolic outcomes in the millions living with chronic HCV. This hypothesis-generating, observational analysis seeks to examine paired changes in thyroid function during HCV infection (HCVi) and after sustained virologic response (SVR) achieved with DAA therapy, independent of interferon exposure. Twenty-nine patients with chronic HCVi at the National Institutes of Health Clinical Center enrolled between 29 May 2015 and 11 March 2016, underwent sofosbuvir/velpatasivr therapy to achieve SVR. Twenty-four returned for post-SVR evaluation and five were excluded for levothyroxine use. Thyroid function, assessed via serum thyroid-stimulating hormone (TSH) using immunoassay and relative thyroxine (T4) levels via non-targeted metabolomics, was measured during infection and approximately 1 year after SVR. Paired analyses were performed in patients with measurements at both time points. Patients were stratified as cirrhotic (C) or non-cirrhotic (NC), classified based on Ishak Fibrosis (IF) score from percutaneous liver biopsy. Among 24 patients with follow-up, 15 had paired TSH measurements (median age 59, 66.7% male, 42.1% C). During HCVi, TSH was significantly lower (median 2.01 vs. 2.27 mIU/L, P<0.001) and relative T4 levels were significantly higher (P<0.001) compared to post-SVR values. TSH remained within the reference range at all time points. Significantly reduced TSH and elevated T4 was observed in NC only patients, while only T4 was significantly altered in the C only patients. TSH and T4 did not differ significantly between Cs and NCs at either time point. HCVi was associated with modest but reversible alterations in thyroid hormone homeostasis. These findings suggest that HCVi is associated with subtle but reversible alterations in thyroid hormone homeostasis. Although values remained within reference ranges, these consistent shifts may support consideration of longitudinal thyroid monitoring in patients with HCV, meriting further investigation into mechanisms and clinical implications.