Over-and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study

Objective: This study investigated the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over-and under-treatment with respect to mortality. Patients and Methods: This was a register-based cohort study of 235,168 individuals who had at least one serum thyrotropin (TSH) during 1995-2011 (median follow-up 7.2 years). Hypothyroidism was defined as at least two measurements of TSH >4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH >4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, sex, and comorbidities using the Charlson Comorbidity Index. Results: Mortality was increased in untreated hypothyroid individuals (n = 673; hazard ratio [HR] = 1.46 [confidence interval (CI) 1.26-1.69]; p < 0.001) compared to euthyroid controls. Results remained significant even when subdividing according to mild (TSH >4.0 mIU/L and ≤10 mIU/L; p < 0.001) and marked hypothyroidism (TSH >10 mIU/L; p = 0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH (HR = 1.05 [CI 1.02-1.07], p < 0.0001, and HR = 1.05 [CI 1.02-1.07], p = 0.0009, respectively). In patients who received levothyroxine, the HR for mortality increased by a factor 1.18 ([CI 1.15-1.21]; p < 0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (older and younger than 65 years). Conclusions: Mortality was increased in untreated but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy.