Excess Mortality in Hyperthyroidism: The Influence of Preexisting Comorbidity and Genetic Confounding: A Danish Nationwide Register-Based Cohort Study of Twins and Singletons

Abstract

Context: Hyperthyroidism is associated with severe comorbidity, such as stroke, and seems to confer increased mortality. However, it is unknown whether this increased mortality is explained by hyperthyroidism per se, comorbidity, and/or genetic confounding. Objective: The objective of the study was to investigate whether hyperthyroidism is associated with an increased mortality and, if so, whether the association is influenced by comorbidity and/or genetic confounding. Methods: This was an observational cohort study using record-linkage data from nationwide Danish health registers. We identified 4850 singletons and 926 twins from same-sex pairs diagnosed with hyperthyroidism. Each case was matched with four controls for age and gender. The Charlson score was calculated from discharge diagnoses on an individual level to measure comorbidity. Cases and controls were followed up for a mean of 10 yr (range 0–31 yr), and the hazard ratio (HR) for mortality was calculated using Cox regression analyses. Results: In singletons there was a significantly higher mortality in individuals diagnosed with hyperthyroidism than in controls [HR 1.37; 95% confidence interval (CI) 1.30–1.46]. This persisted after adjustment for preexisting comorbidity (HR 1,28; 95% CI 1.21–1.36). In twin pairs discordant for hyperthyroidism (625 pairs), the twin with hyperthyroidism had an increased mortality compared with the corresponding cotwin (HR 1.43; 95% CI 1.09–1.88). However, this was found only in dizygotic pairs (HR 1.80; 95% CI 1.27–2.55) but not in monozygotic pairs (HR 0.95; 95% CI 0.60–1.50). Conclusions: Hyperthyroidism is associated with an increased mortality independent of preexisting comorbidity. The study of twin pairs discordant for hyperthyroidism suggests that genetic confounding influences the association between hyperthyroidism and mortality.