Clinical Characteristics and Outcomes of Graves' Disease in Individuals with Prior Hypothyroidism

Context Transition from hypothyroidism to Graves' disease (GD) is uncommon. Objective To compare presentation, management, and outcomes of GD after hypothyroidism (post-hypo-GD) with GD controls (no prior thyroid disease). Design Retrospective cohort 2010 to 2022, followed through October 2024. Setting Maccabi Healthcare Services, Israeli health maintenance organization. Patients Adults with incident GD and thyroid-stimulating immunoglobulin activity ≥140% within 1 year of thyrotoxicosis (N = 2402, 256 post-hypo-GD, 2146 GD controls). Excluded prior or current amiodarone users. Interventions Longitudinal assessment of usual care with antithyroid drugs, radioactive iodine, or total thyroidectomy, and subsequent hypothyroidism requiring levothyroxine. Main Outcome Measures Usual care treatments and incident hypothyroidism requiring levothyroxine. Results Compared to GD controls, post-hypo-GD patients were older (51.4 ± 14.3 vs 47.4 ± 13.6 years, P <.001), predominantly female (88.2% vs 76.9%, P <.001), and with higher prevalence of autoimmune disease (19.5% vs 12.9%, P =.003). At diagnosis, post-hypo-GD patients had milder disease with lower median free T4 (21.7 vs 26.8 pmol/L, P <.001) and free T3 (8.5 vs 10.4 pmol/L, P <.001) levels. Over a 7.2-year median follow-up, post-hypo-GD patients were less frequently treated with antithyroid drugs (65.6% vs 81.0%, P <.001). Radioactive iodine ablation and total thyroidectomy use were comparable. Post-hypo-GD patients were more than twice as likely to develop hypothyroidism requiring levothyroxine at the end of follow-up (41.8% vs 21.0%, P <.001). Conclusion Post-hypo-GD (∼10% of new GD cases) is a distinct, predominantly female phenotype marked by milder thyrotoxicosis, lower antithyroid drug use, and a high rate of relapse into hypothyroidism warranting routine assessment of prior thyroid status and close biochemical monitoring.