Assessment of thyroid function: towards an integrated laboratory--clinical approach

Abstract

Laboratory assessment of thyroid function is now often initiated with a low pre-test probability, by clinicians who may not have a detailed knowledge of current methodology or testing strategies. Skilled laboratory staff can significantly enhance the choice of appropriate tests and the accuracy of clinical response; such involvement requires both appropriate training and relevant information from the clinician. Measurement of the serum thyroid stimulating hormone (TSH) concentration with an assay of adequate sensitivity is now the cornerstone of thyroid function testing; for untreated populations at risk of primary thyroid dysfunction, a normal TSH concentration rules out an abnormality with a high degree of certainty. However, in several important situations, most notably pituitary abnormalities and early treatment of thyroid dysfunction, serum TSH can give a misleading indication of thyroid status. An abnormal TSH concentration alone is never an adequate basis for initiation of treatment, which should be based on the typical relationship between trophic and target gland hormones, based on serum TSH and an estimate of serum free thyroxine (T4). Six basic assumptions, some clinical, some laboratory-based, need to be considered, together with the relevant limiting conditions, for reliable use of this relationship. Current methods of free T4 estimation remain imperfect, especially during critical illness. Diagnostic approach differs significantly between initial diagnosis and follow-up of treated thyroid dysfunction. In some situations, serum triiodothyronine (T3) is also required, but serum T3 lacks sensitivity for diagnosis of hypothyroidism, and has poor specificity during non-thyroidal illness. Where assay results are anomalous, most atypical findings can be resolved by attention to the clinical context, without further investigation.

Figure 1

Effect of addition of frusemide to normal serum on estimates of free T4 using three commercial free T4 methods that involve varying degrees of sample dilution. The effect of the competitor is progressively obscured with increasing sample dilution. Redrawn from reference .

Figure 2

Mechanism of heparin-induced increase in apparent serum free T4. Heparin acts in vivo (left) to liberate lipoprotein lipase from vascular endothelium. Lipase acts in vitro to increase the concentration of non-esterified fatty acids; concentrations above 2–3 mmol/L displace of T4 and T3 from TBG. This effect is accentuated by low serum albumin and high triglyceride concentrations and by sample incubation at 37°C.

Figure 3

The relationship between serum TSH and total free T4 concentrations in normal subjects (N) and in various typical abnormalities of thyroid function: primary hypothyroidism (A); central or pituitary-dependent hypothyroidism (B); thyrotoxicosis due to autonomy or abnormal thyroid stimulation (C); and TSH-dependent thyrotoxicosis or generalised thyroid hormone resistance (D). Note that linear free and total T4 responses correspond to logarithmic TSH changes. Findings at A and C represent primary thyroid abnormalities, while results in areas B and D suggest a primary pituitary abnormality. Results in the intermediate areas are most often due to non-steady state sampling conditions, or an altered T4 -TSH relationship.

Figure 4

Algorithm for the assessment of thyroid function based on initial assay of serum TSH. Abnormal TSH values lead to further assays as shown. Assays of free T4 are always required if pituitary dysfunction is suspected, during the early treatment of thyroid dysfunction, during critical illness and with the use of drugs that influence the pituitary-thyroid axis. (* Further testing is indicated if pituitary dysfunction is known or suspected, during critical illness and in the first 6–12 months of treatment for thyroid dysfunction).

Figure 5

Serial changes in serum free T4 and TSH in response to T4 replacement in a patient with longstanding severe untreated primary hypothyroidism without evidence of pituitary enlargement or tumour. Normalization of serum TSH lagged 7–10 months behind normalization of serum free T4.

Figure 6

Free T4 estimates by six different kit methods in euthyroid patients after bone marrow transplantation. Therapy included heparin and glucocorticoids. Mean values are normalized to 100%, with reference limits shown by the boxes. A high proportion of free T4 estimates are abnormal, either increased or decreased, depending on the method. Serum total T4 remained normal in 19 of the 20 study subjects, while serum TSH was subnormal in 11, independent of the method. Redrawn from reference .