Subclinical thyroid disease is very common, particularly in elderly people. Recognition of this endocrine disorder is increasing, partly due to a large increase in thyroid function testing, especially in primary care. Many cross-sectional studies have investigated whether subclinical hyperthyroidism or subclinical hypothyroidism are associated with specific symptoms, signs, or comorbidities, and a smaller number of prospective studies have examined whether subclinical thyroid disease predicts specific adverse outcomes.1
What is the latest evidence driving the need, or otherwise, for therapeutic intervention in these common, and largely asymptomatic, biochemically defined disorders? A large and seemingly irrefutable body of evidence exists supporting the association of subclinical hyperthyroidism with atrial fibrillation risk, especially when thyroid-stimulating hormone (TSH) is at undetectable concentrations.2, 3 Subclinical hyperthyroidism is also associated with other adverse cardiac outcomes, such as coronary heart disease events and mortality, and heart failure. Evidence linking cardiovascular disorders with tests of thyroid function within the reference range, including higher circulating free thyroxine concentrations,4 suggests that the cardiovascular system is particularly sensitive to subtle changes in thyroid status. Thus, the cardiovascular system is the most important physiological system for which to consider risk, and, in turn, with the potential to benefit from treatment.
If the evidence for risk association with cardiovascular endpoints is strong, why is there controversy about intervention? Several crucial reasons exist. First, association does not prove causation, and many studies have not fully considered potential confounders for comorbidities in conditions such as coronary heart disease and heart failure. Second, nearly all studies have been based on one or two TSH measurements in individual subjects, but low TSH is often transient, especially when only slightly low, and frequently reflects non-thyroidal illnesses or drugs, rather than underlying thyroid disease such as mild Graves’ disease or toxic nodular hyperthyroidism. Third, intervention for subclinical hyperthyroidism means radioiodine therapy or antithyroid drugs, neither of which is trivial. Radioiodine is generally considered the treatment of choice for toxic nodular disease (the most common underlying thyroid diagnosis, in view of the typical age when subclinical hyperthyroidism is diagnosed). Radioiodine treatment often results in hypothyroidism and the need for permanent thyroxine replacement. Since up to half of patients taking thyroxine have subclinical hyperthyroidism or hypothyroidism biochemically, subclinical hyperthyroidism can be perpetuated or replaced with subclinical hypothyroidism. Finally, there have been no randomised controlled trials of treatment of subclinical hyperthyroidism with meaningful clinical endpoints. Two trials were stopped because of low recruitment and a third has recruitment that is lower than planned, although it is continuing. These issues were described in a recent article about the problems encountered with such trials.4 Despite this absence of evidence, expert groups recommend that treatment should be strongly considered, especially in elderly patients;5 surveys of practice show this is occurring. It seems extraordinary that evidence that the benefit of treatment outweighs the risk does not exist in the 21st century for such a common disorder. We can only hope that evidence will accrue in the next few years.
The situation regarding subclinical hypothyroidism is probably more complex and controversial than that for subclinical hyperthyroidism. The most relevant physiological system is again cardiovascular; the largest meta-analysis performed so far reports an association with cardiovascular mortality in more severe cases (ie, serum TSH >10 mIU/L).6 Again, raised TSH is frequently transient, although a persistent increase is a more specific indicator of underlying thyroid disease. However, the upper limit of the TSH reference range rises with age,7 leading to controversy about the definition of disease, especially if TSH is in the 5—10 mIU/L range in elderly people. Randomised controlled trials of treatment (thyroxine replacement) have been done, but these are largely small, heterogeneous, and underpowered, and their findings are unsurprisingly negative or conflicting. A Cochrane review indicated insufficient evidence to recommend for, or against, treatment, including in those with a TSH greater than 10 mIU/L and in very elderly patients.8 However, new evidence9 exists for improved outcomes of coronary heart disease in younger, but not older, patients treated with thyroxine, and there are new data10 showing that thyroxine treatment helps to preserve renal function in people with subclinical hypothyroidism and chronic kidney disease. Fortunately, several clinically relevant trials are underway—including one EU-funded multicentre study of patients older than 80 years that will examine cardiovascular and quality-of-life outcomes—so the evidence base for subclinical hypothyroidism should increase and better guide us in our therapeutic approach.
1 Cooper DS, Biondi B. Subclinical thyroid disease. Lancet 2012; 379: 1142-1154. Summary | Full Text | PDF(416KB) |CrossRef | PubMed
2 Collet TH, Gussekloo J, Bauer DC, et al. Subclinical hyperthyroidism and the risk of coronary heart disease and mortality.Arch Intern Med 2012; 172: 799-809. CrossRef | PubMed
3 Gammage MD, Parle JV, Holder RL, et al. Association between serum free thyroxine concentration and atrial fibrillation.Arch Intern Med 2007; 167: 928-934. CrossRef | PubMed
4 Goichot B, Pearce SH. Subclinical thyroid disease: time to enter the age of evidence-based medicine. Thyroid 2012; 22:765-768. CrossRef | PubMed
5 Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Endocr Pract 2011; 17: 456-520.CrossRef | PubMed
6 Rodondi N, den Elzen WP, Bauer DC, et al. Subclinical hypothyroidism and the risk of coronary heart disease and mortality.JAMA 2010; 304: 1365-1374. CrossRef | PubMed
7 Waring AC, Arnold AM, Newman AB, Buzkova P, Hirsch C, Cappola AR. Longitudinal changes in thyroid function in the oldest old and survival: the cardiovascular health study all-stars study. J Clin Endocrinol Metab 2012; 97: 3944-3950.CrossRef | PubMed
8 Villar HC, Saconato H, Valente O, Atallah AN. Thyroid hormone replacement for subclinical hypothyroidism. Cochrane Database Syst Rev 2007; 3. CD003419
9 Razvi S, Weaver JU, Butler TJ, Pearce SH. Levothyroxine treatment of subclinical hypothyroidism, fatal and nonfatal cardiovascular events, and mortality. Arch Intern Med 2012; 172: 811-817. CrossRef | PubMed
10 Shin DH, Lee MJ, Kim SJ, et al. Preservation of renal function by thyroid hormone replacement therapy in chronic kidney disease patients with subclinical hypothyroidism. J Clin Endocrinol Metab 2012; 97: 2732-2740. CrossRef | PubMed