Chronic HCV Infection and the Endocrine-Metabolic Axis: A Systematic Review of Extrahepatic Manifestations

<title>Abstract</title> <p> <bold>Introduction</bold> Chronic hepatitis C virus (HCV) infection produces extrahepatic manifestations extending beyond insulin resistance, involving thyroid, adipokine, bone, and gonadal axes, yet this broader endocrine-metabolic burden has not been systematically consolidated. <bold>Objective</bold> To synthesize evidence on the association between chronic HCV infection and endocrine-metabolic disturbances across glycemic, thyroid, adipokine, bone, and sexual-function domains. <bold>Methods</bold> A systematic review following PRISMA 2020 guidelines was conducted across PubMed, Embase, Scopus, and CENTRAL from inception through July 2026. Observational and previously published meta-analytic studies reporting endocrine-metabolic outcomes in chronic HCV monoinfection were eligible. Risk of bias was assessed using the Newcastle-Ottawa Scale. Quantitative pooling was performed only when at least two comparable studies were available for the same outcome and comparator. <bold>Results</bold> Of 4,945 records screened, 21 studies met eligibility criteria across eight domains: type 2 diabetes (n = 2), insulin resistance (n = 3), thyroid dysfunction (n = 4), adipokines (n = 1), leptin (n = 4), adiponectin (n = 1), bone mineral density (n = 3), and sexual dysfunction (n = 3); no eligible data addressed hypogonadism. Previously pooled estimates showed increased risk of type 2 diabetes (OR 1.68, 95% CI 1.15–2.20) and hypothyroidism (OR 3.10, 95% CI 2.19–4.40) in HCV-infected populations. Individual studies reported elevated insulin resistance prevalence, HCV-genotype-dependent leptin alterations, reduced bone mineral density, and sexual dysfunction affecting up to 72.8% of infected men, though heterogeneous comparators precluded de novo pooling for most domains. <bold>Conclusion</bold> Chronic HCV infection is associated with a multisystem endocrine-metabolic phenotype extending well beyond glycemic dysregulation, though evidence density and comparability remain limited outside diabetes and thyroid outcomes, warranting standardized prospective studies. </p>