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 2010-2022, 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 (ATD), radioactive iodine (RAI), or total thyroidectomy, and subsequent hypothyroidism requiring levothyroxine.

Main outcome measures: Use of 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<0.001), predominantly female (88.2% vs. 76.9%, p<0.001), and with higher prevalence of autoimmune disease (19.5% vs. 12.9%, p=0.003). At diagnosis, post-hypo-GD patients had milder disease with lower median free thyroxine (fT4) (21.7 vs. 26.8 pmol/L, p<0.001) and free triiodothyronine (fT3) (8.5 vs. 10.4 pmol/L, p<0.001) levels. Over a 7.2-year median follow-up, post-hypo-GD patients were less frequently treated with ATDs (65.6% vs. 81.0%, p<0.001). RAI 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<0.001).

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.