Abstract
BACKGROUND: In iodine-replete populations, hypothyroidism is mainly caused by autoimmune thyroiditis, which disproportionately affects females. Ultra-processed foods (UPFs) are linked to metabolic disturbances and chronic inflammation that may contribute to autoimmune-related hypothyroidism; however, evidence remains limited, particularly regarding sex-specific differences.
OBJECTIVES: To examine the association between UPF intake and incident autoimmune-related hypothyroidism, and quantify mediation by circulating biomarkers, with emphasis on sex-specific effects.
METHODS: We included 123,812 UK Biobank participants (68,456 females; 55,356 males) without thyroid disease at baseline who completed ≥2 24-h dietary recalls (2009-2012). UPF intake (percentage energy) was defined according to NOVA and modeled in sex-specific quintiles. Incident hypothyroidism was identified via linked health records to 2020. Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs), adjusting for demographic, lifestyle, clinical, and dietary factors. Mediation analyses assessed the proportion of mediation via biomarkers involving renal, liver function, lipid, glucose metabolism, and immune-inflammatory status. Effect modification was evaluated by including cross-product interaction terms between UPF intake and potential modifiers.
RESULTS: During a median of 11.2 y of follow-up, 2907 hypothyroidism cases occurred (2303 females; 604 males). Compared with the lowest UPF quintile, the highest quintile showed a higher risk of hypothyroidism (HR: 1.31; 95% confidence interval: 1.16, 1.49; P-trend < 0.001), consistent in females [1.28 (1.11, 1.48)] and males [1.36 (1.04, 1.79)]. Renal function biomarker cystatin C mediated the largest proportion of the association (35.5% in females; 26.3% in males), followed by cholesterol efflux-related biomarkers (apolipoprotein A and high-density lipoprotein cholesterol). Among females, associations were stronger with hormone replacement therapy (interaction HR: 1.06, P-interaction = 0.021).
CONCLUSIONS: Higher UPF intake was associated with an increased risk of autoimmune-related hypothyroidism in both sexes, partly mediated by renal and lipid biomarkers. Risk may be amplified in females using hormone replacement therapy.