Conclusions In patients with a diagnosis of hypothyroidism, no evidence was found to suggest a clinically meaningful difference in the pattern of long term health outcomes (all cause mortality, atrial fibrillation, ischaemic heart disease, heart failure, stroke/transient ischaemic attack, fractures) when TSH concentrations were within recommended normal limits. Evidence was found for adverse health outcomes when TSH concentration is outside this range, particularly above the upper reference value.

Results 162 369 patients with hypothyroidism and 863 072 TSH measurements were included in the analysis. Compared with the reference TSH category (2-2.5 mIU/L), risk of ischaemic heart disease and heart failure increased at high TSH concentrations (>10 mIU/L) (hazard ratio 1.18 (95% confidence interval 1.02 to 1.38; P=0.03) and 1.42 (1.21 to 1.67; P<0.001), respectively). A protective effect for heart failure was seen at low TSH concentrations (hazard ratio 0.79 (0.64 to 0.99; P=0.04) for TSH <0.1 mIU/L and 0.76 (0.62 to 0.92; P=0.006) for 0.1-0.4 mIU/L). Increased mortality was observed in both the lowest and highest TSH categories (hazard ratio 1.18 (1.08 to 1.28; P<0.001), 1.29 (1.22 to 1.36; P<0.001), and 2.21 (2.07 to 2.36; P<0.001) for TSH <0.1 mIU/L, 4-10 mIU/L, and >10 mIU/L. An increase in the risk of fragility fractures was observed in patients in the highest TSH category (>10 mIU/L) (hazard ratio 1.15 (1.01 to 1.31; P=0.03)).

Introduction

Hypothyroidism is a highly prevalent global health problem that can substantially affect patients’ wellbeing.1 Lifelong treatment with thyroid hormone (replacement therapy) is needed when the diagnosis of persistent thyroid hormone deficiency is confirmed; consequently, levothyroxine is one of the most commonly prescribed drugs in Western countries,23 and this is likely to increase further in the foreseeable future.4

Long term adverse health outcomes in patients with thyroid dysfunction and treatment targets to optimise these outcomes, generally monitored by serial measurements of thyroid stimulating hormone (TSH), have been extensively investigated. In particular, the cardiovascular effect of thyroid dysfunction and the negative ramifications of clinical (overt) thyroid hypofunction, mediated by changes in systemic vascular resistance, hypertension, hypercholesterolaemia, and accelerated atherosclerosis, are well documented.56 One of the targets for treatment with thyroid hormone replacement is to reverse such adverse effects. Current guidelines in Europe and the US recommend that replacement therapy should be aimed at resolving symptoms and achieving “normalisation” of TSH.78 However, no specific optimal target for TSH exists in the context of thyroid hormone replacement. This uncertainty is reflected in the guidelines proposed by the American Thyroid Association Task Force and the statement issued by the British Thyroid Association Executive Committee, which suggest a wide range for TSH, 0.4-4.0 mIU/L, as an indication for optimal replacement,78 after emphasising the scarcity of relevant evidence. TSH concentrations in this wide target range may be achieved by different doses of levothyroxine. However, from a physiological standpoint, a continuum of effects may plausibly occur across the spectrum of normal TSH concentrations9; the same human heart might behave differently at a pace dictated by a TSH concentration of 0.4 mIU/L compared with one of 4 mIU/L, both of which are considered normal. Evidence indicates that TSH and circulating thyroid hormone concentrations are quite tightly regulated on an individual basis,10 but determining an individual’s set point is not part of routine clinical practice, and replacement treatment is generally targeted in a wide reference range.

Although age specific TSH targets may be considered, especially in the context of high cardiovascular risk,7 this strategy is based on the findings of studies in euthyroid or subclinically hypothyroid people. However, patients with hypothyroidism need a higher concentration of serum free thyroxine to achieve a normal TSH concentration compared with euthyroid controls.11 Consequently, a hypothyroid patient receiving thyroid replacement therapy and a euthyroid patient with comparable TSH concentrations are not expected to have comparable circulating free thyroxine concentrations. The same is true of free triiodothyronine concentrations in patients who have had total thyroidectomy.12 Therefore, any extrapolations on the association between optimal TSH concentrations and cardiovascular outcomes in patients receiving thyroid replacement therapy based on studies in euthyroid patients should be treated with caution, as serum free thyroxine and free triiodothyronine concentrations (relevant to cardiovascular physiology) may differ significantly between the two groups.

Moreover, in primary studies in euthyroid or subclinically hypothyroid patients,13 and in the related meta-analyses and reviews,14151617181920 thyroid function testing was done only at baseline. The potential therefore exists for misclassification bias in all estimates to date as a result of established and anticipated changes in thyroid hormone production over the life course of a patient, as well as instances of transient thyroid dysfunction (such as non-thyroidal illness or following the hyperthyroid phase of a painless thyroiditis). A person classified as euthyroid at baseline might go on to develop hypothyroidism, overt or subclinical, whereas those classified as subclinically hypothyroid might be found to be euthyroid on follow-up thyroid function testing.

Similar limitations affect studies assessing the association between thyroid dysfunction and risk of fracture,2122 and whether variation in TSH concentration within normal limits may significantly affect the skeleton or whether any effect is insignificant in clinical terms (fracture risk remains unaffected) remains unclear. This is further challenged by evidence suggesting that free thyroxine concentrations are the main driver of the above clinical outcomes.2324

The aim of this study was to explore whether TSH concentration is associated with an increased risk of cardiovascular diseases, mortality, and fractures in patients with a diagnosis of hypothyroidism. We treated TSH as a time varying covariate to account for variation in TSH concentration over time within individuals.