The normal TSH reference range: what has changed in the last decade?

Serum TSH assessment is the most sensitive screening test for the diagnosis of thyroid dysfunction in the absence of pituitary or hypothalamic disease. This test has been used increasingly in the last decade to detect subclinical thyroid dysfunction (STD). Recent data suggest that STD is a common disorder that may be associated with important adverse events (1–5). The American Association of Clinical Endocrinologists (AACE) and American Thyroid Association (ATA) 2012 guidelines recommend treatment of subjects with persistent increased serum TSH levels 10 mIU/L and undetectable serum TSH ( 0.1 mIU/L) (6, 7). The treatment of mild thyroid hormone excess (TSH 0.1–0.4 mIU/L) ordeficiency (serumTSH 10mIU/L) is controversial (1,2). However, what is the normal TSH reference range? Obviously, this issue is critical in deciding whether or not to treat patients with mild STD and in identifying individuals with high-normal or low-normal serum TSH. It is also important in defining the TSH target level in patients receiving thyroid hormone replacement therapy. In 2002, the National Health and Nutrition Examination Survey (NHANES) III, a US population-based study, evaluated the normal TSH range in the “thyroid disease-free adult population” (8). Theauthors excludedsubjectswith risk factorsandafamilyhistoryofthyroiddysfunction,self-reported thyroid disease or goiter, and thyroid autoimmunity. The study suggested that 95% of the US disease-free population had a serum TSH concentration between 0.45 and 4.12 mIU/L (8). However, TSH values did not have a Gaussian distribution because the curve was skewed by individuals with occult autoimmune thyroid dysfunction despite negative thyroid peroxidase antibodies (9). In 2005, the National Academy of Clinical Biochemistry (NACB) recommended that thyroidultrasonographybeperformedineuthyroidsubjects to exclude the presence of occult thyroid autoimmunity in order to define the serum TSH reference interval more accurately (10). They suggested that the upper limit of the TSH reference range be lowered to 2.5 mIU/L (10). The upper and lower limits of the normal serum TSH concentration continue to be debated by expert clinical thyroidologists. In 2005, two back-to-back articles appeared in the JCEM: one article, by Wartofsky and Dickey (11), favored a narrower TSH reference range, but according to the other, by Surks et al (12), the TSH range should remain unchanged. It should be mentioned that the sensitivity and specificity of TSH assays can affect the evaluation of serum TSH because some assays may detect biologically inactive circulating TSH isoforms (1). The upper TSH reference limit has progressively declined over the last decade thanks to more sensitive TSH assays, more accurate thyroid antibody tests, and a more accurate selection of the reference population. Different TSH cut-off limits have been reported in population-based studies conducted in various countries (1). Subsequent findings confirmed that ethnicity, iodine intake, gender, age, and body mass index can influence the reference range of serum TSH. In fact, the normal TSH upper limit was lower in African Americans (3.6 mIU/L) than in Mexican Americans or Caucasians (4.2 mIU/L) (8). Reanalysis of these data 5 years later showed that the upper limit of normal serum TSH at the 97.5th percentile was 3.5 mIU/L in individuals 20–29 years old, 4.5 mIU/L in those 50–59 years old, and 7.5 mIU/L in those older than 80 years (13). Variations in thyroid function within the reference range have been associated with body weight in several cross-sectional and longitudinal studies (14). Moreover, serum TSH levels at the upper limit of the normal range have been found in obese adults and have been positively correlated with body mass index (14).