Thyrotropin/Thyroid Stimulating Hormone (TSH) Measurement

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TSH Reference Intervals

Despite some gender, age and ethnicity-related differences in TSH levels revealed by the recently published NHANES III US survey, it is not considered necessary to adjust the reference interval for these factors in clinical practice.[18] Serum TSH levels exhibit a diurnal variation with the peak occurring during the night and the nadir, which approximates to 50% of the peak value, occurring between 1000 and 1600 hours.[123,124] This biologic variation does not influence the diagnostic interpretation of the test result since most clinical TSH measurements are performed on ambulatory patients between 0800 and 1800 hours and TSH reference intervals are established from specimens collected during this time period. Serum TSH reference intervals should be established using specimens from TPOAb-negative, ambulatory, euthyroid subjects who have no personal or family history of thyroid dysfunction and no visible goiter. The variation in the reference intervals for different methods reflects differences in epitope recognition of different TSH isoforms by the different kit reagents and the rigor applied to the selection of appropriate normal subjects.

Serum TSH concentrations determined in normal euthyroid subjects are skewed with a relatively long "tail" towards the higher values of the distribution. The values become more normally distributed when they are logtransformed. For reference range calculations, it is customary to log-transform the TSH results to calculate the 95% reference interval (typical population mean value ~1.5 mIU/L, range 0.4 to 4.0 mIU/L in iodide-sufficient populations).[202,206] However, given the high prevalence of mild (subclinical) hypothyroidism in the general population, it is likely that the current upper limit of the population reference range is skewed by the inclusion of persons with occult thyroid dysfunction.[18]

Guideline 22. TSH Reference Intervals

TSH reference intervals should be established from the 95 % confidence limits of the log-transformed values of at least 120 rigorously screened normal euthyroid volunteers who have:

  • No detectable thyroid autoantibodies, TPOAb or TgAb (measured by sensitive immunoassay)

  • No personal or family history of thyroid dysfunction

  • No visible or palpable goiter

  • No medications (except estrogen).

Over the last two decades, the upper reference limit for TSH has steadily declined from ~10 to approximately ~4.0-4.5 mIU/L. This decrease reflects a number of factors including the improved sensitivity and specificity of current monoclonal antibody based immunometric assays, the recognition that normal TSH values are logdistributed and importantly, improvements in the sensitivity and specificity of the thyroid antibody tests that are used to pre-screen subjects. The recent follow-up study of the Whickham cohort has found that individuals with a serum TSH >2.0 mIU/L at their primary evaluation had an increased odds ratio of developing hypothyroidism over the next 20 years, especially if thyroid antibodies were elevated.[35] An increased odds-ratio for hypothyroidism was even seen in antibody-negative subjects. It is likely that such subjects had low levels of thyroid antibodies that could not be detected by the insensitive microsomal antibody agglutination tests used in the initial study.[207] Even the current sensitive TPOAb immunoassays may not identify all individuals with occult thyroid insufficiency. In the future, it is likely that the upper limit of the serum TSH euthyroid reference range will be reduced to 2.5 mIU/L because >95% of rigorously screened normal euthyroid volunteers have serum TSH values between 0.4 and 2.5 mIU/L.

Before the immunometric assay era, TSH methods were too insensitive to detect values in the lower end of the reference range.[209] Current methods however, are capable of measuring TSH at the lower end and now cite lower limits between 0.2 and 0.4 mIU/L.[202] As the sensitivity of the methods has improved, there has been an increased interest in defining the true lower limit of normal to better determine the presence of mild (subclinical) hyperthyroidism. Current studies suggest that TSH values in the 0.1 to 0.4 mIU/L range may represent thyroid hormone excess and in elderly patients might be associated with an increased risk of atrial fibrillation, and cardiovascular mortality.[36,37] It is therefore important to carefully exclude subjects with a goiter and any illness or stress in the normal cohort selected for reference range study.

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