Thyroid Function Testing – A Review

Review Article

Annals Thyroid Res. 2014;1(2): 17-22.

Thyroid Function Testing – A Review

Huang HL1 and Aw TC2*

1Department of Nuclear Medicine and PET, Singapore General Hospital, Singapore

2Department of Lab Medicine, Changi General Hospital, Singapore

*Corresponding author: Aw TC, Department of Lab Medicine, Changi General Hospital, 2 Simei Street 3, Singapore 529889, Singapore

Received: November 01, 2014; Accepted: November 11, 2014; Published: November 12, 2014


Thyroid function testing is common and the indications for their use are increasing. This review explores the indications and components of thyroid testing. A panel consisting of thyroid stimulating hormone and free thyroxine should form the first line of diagnostic tests. Further differentiation of various pathologies can be made with thyroid antibodies or radio uptake scanning. For the follow up of differentiated thyroid cancer serum thyroglobulin serves as a biomarker. The sensible use of thyroid function tests and their interpretation requires sufficient understanding of clinical medicine and laboratory science.

Keywords: Thyroid function testing; TSH; Free thyroxine


TFT: Thyroid Function Tests; DTC: Differentiated Thyroid Cancer; TSH: Thyroid Stimulating Hormone; TRH: Thyrotropin Releasing Hormone; T4: Thyroxine; fT4: Free Thyroxine; T3: Triiodothyronine; fT3: Free T3; TPO-Ab: Thyroid Peroxidise Antibodies; Tg-Ab: Thyroglobulin Antibodies; Tg: Thyroglobulin; TSHoma: TSH Secreting Pituitary Adenoma; RTH: Resistance to Thyroid Hormone; NTI: Non-Thyroidal Illness; HPT: Hypothalamic- Pituitary-Thyroid; TRH: Thyrotropin Releasing Hormone


Thyroid function testing constitutes the most frequent endocrine tests requested of a clinical laboratory [1,2]. An understanding of the components of thyroid testing and the indications for each is essential in aiding clinical diagnosis and influencing the management of a diverse range of thyroid related conditions. This review aims to provide a brief scientific update for practicing doctors and a small dose of clinical medicine for scientists. It will not include testing for perinatal thyroid disorders, thyroid nodules and thyroid cancer as these subjects merit more detailed consideration separately. The rarer causes of thyroid dysfunction (TSH secreting pituitary adenomas – TSHomas, thyroid hormone resistance syndromes – RTH) and Familial Dysalbuminemic Hyperthyroxinemia (FDH) will be mentioned briefly as these conditions may confound the results of and the interpretation of Thyroid Function Tests (TFT).


Thyroid hormone excess and deficiency can present in a diverse manner, thus adequate and accurate laboratory assessment is vital. Thyroid dysfunction is associated with adverse cardiovascular and skeletal outcomes [3]. Thyroid testing can provide an objective diagnosis in most instances of sometimes subtle or uncommon clinical manifestations of disease. Treatment may include ablative therapy (surgery or radio-iodine) and long term (anti-thyroid drugs) or life-long (thyroid hormone replacement) medications. Frequent monitoring of these patients is required. Thyroid disorders are common. In the US national health survey 4.6% of the population had hypothyroidism (0.3% overt and 4.3% subclinical) and 1.3% had hyperthyroidism (0.5% overt and 0.7% subclinical) [4]. Thyroid cancer is also becoming more common through increased detection via imaging. Differentiated Thyroid Cancer (DTC) has a relatively favourable prognosis if treated and monitored properly. The clinical use of thyroid testing in a general practice has increased by 50% over the last decade [5]. Radionuclide thyroid uptake testing may occasionally be needed to evaluate the functional status of thyroid tissue [6].

Thyroid hormones (T4 and T3) are regulated by pituitary TSH. In turn, TSH is controlled by the interaction between feedback inhibition by thyroid hormones and hypothalamic Thyrotropin Releasing Hormone (TRH) [7]. The relationship between TSH and fT4 is inversely loglinear such that a small change in fT4 is accompanied by a large reciprocal change in TSH [8]. Each individual has a genetically determined unique set point for the TSH/free T4 relationship [9]. In early thyroid dysfunction, TSH responds to this set-point wherein the fT4 is normal while TSH is depressed (subclinical hyperthyroidism) and vice versa in subclinical hypothyroidism (elevated TSH and normal fT4) [10-12]. The concentration of thyroid analytes varies widely within individuals as well as between individuals.


Thyroid Function Tests (TFT) are used as screening tools, to confirm clinical diagnoses, to assess adequacy of therapy, and to monitor treatment of DTC. Thyroid function is best assessed by measuring TSH when pituitary or hypothalamic disease is absent. In addition, patients should not be on drugs which can affect the thyroid [13]. Metformin (commonly prescribed for type 2 diabetes mellitus) can cause a significant reduction in TSH levels [14,15].


Routine TFT screen in an asymptomatic subject is controversial [16] though this was proposed by the American Thyroid Association in 2000 [17]. However, a new systematic review has found no evidence on benefits and harms of screening versus not screening [18]. However, screening can identify subjects with subclinical thyroid dysfunction as well as undiagnosed overt thyroid disease. TFT may be indicated for subjects at risk for thyroid disease such as women over 50 years, the elderly, those with significant family (thyroid disease) and personal medical history (palpitations, neck irradiation, autoimmune disease), and medications (amiodarone, lithium). For screening, TSH alone will usually suffice. Laboratories can proactively provide reflex fT4 testing when TSH is abnormal instead of a repeat test on another occasion. A normal TSH indicates euthyroidism and no further testing is needed. Thyroid antibodies (thyroid peroxidase and thyroglobulin) may be employed in at-risk subjects to stratify for future thyroid dysfunction.

Screening in hospitalized or ill patients is not recommended unless thyroid disease is strongly suspected since changes in thyroid hormones, binding proteins, and TSH concentrations occur in severe Non-Thyroidal Illness (NTI) [19]. Also known as euthyroid sick syndrome, NTI is a syndrome of abnormal TFT (notably low T3 or fT3), deranged Hypothalamic-Pituitary-Thyroid (HPT) axis, abnormal thyroid hormone binding proteins and impaired thyroid hormone action in the absence of any intrinsic disease of the HPT axis [20]. In NTI, patients are ill or hospitalized and can have dynamic changes in TFT results as illness progresses or recover. Very different fT4-TSH combinations may be encountered underscoring the need to avoid using TFT in hospitalized or ill subjects. In NTI, T4 and TSH levels are usually normal but in severe or prolonged illness low T4 (and fT4) and an inappropriately low normal or decreased TSH (0.1-0.4 mIU/L) may be seen. TSH levels below <0.01 mIU/L are very unusual except in very severe illnesses in the intensive care environment. Early in the course of NTI fT4 may increase followed by progressive decline with disease progression. T3 (and fT3) decline from the onset. Uncommonly, a low TSH and normal fT4 may be seen in NTI and can be distinguished from hyperthyroidism by remembering the clinical milieu and if necessary finding a low T3 (or fT3). Thus the use of both TSH and fT4 is necessary to accurately assess thyroid dysfunction in ill and hospitalized patients.

Diagnosis of thyroid conditions

One of the more common indications for thyroid testing is in the evaluation of clinically suspected thyroid dysfunction. A basic initial screen can include TSH alone but the use of TSH in conjunction with fT4 is preferred [16,21]. Further testing such as for thyroid antibodies, thyroglobulin or even radionuclide uptake studies should follow based on initial test results.

Suspected hyperthyroidism: Hyperthyroidism refers to the excessive production and secretion of thyroid hormones by the thyroid gland. The resulting clinical condition (fatigue, nervousness, weight loss despite normal or enhanced appetite, heat intolerance, palpitations) is termed thyrotoxicosis [21]. While the two terms are often used interchangeably subjects who become thyrotoxic from exogenous thyroid hormones (e.g. surreptitious consumption) are strictly not hyperthyroid and their thyroid hormone production may be suppressed. Older subjects (>60 years) often present with a paucity of symptoms other than weight loss and breathlessness [22].

An algorithm for evaluating suspected hyperthyroidism is provided (Figure 1). A thyroid panel comprising TSH and fT4 will usually suffice. In overt hyperthyroidism TSH is often <0.01 mIU/L (or undetectable) with elevations in both fT4 and fT3. The most common causes of primary hyperthyroidism is Graves disease (an autoimmune disease consequent to stimulatory TSH-receptor antibodies - TRAb), followed by toxic nodular goiter (multinodular or adenoma) and thyroiditis. In thyroiditis preformed thyroid hormones stored in thyroid follicles are released. Thyroiditis of the subacute variety (i.e. de Quervain’s thyroiditis) is characterised by pain and elevated inflammatory markers (sedimentation rate and C-reactive protein) whereas they are normal in painless and druginduced thyroiditis [23]. Most patients with Graves’ disease have obvious presentation (symptoms of thyrotoxicosis, eye signs and a smooth goiter on physical examination). Together with the classical TFT results no further investigations are needed. When presentation is atypical (e.g. euthyroid ophthalmopathy) measurement of TRAb may be helpful [24]. Over 90% of Graves’ disease has positive TRAbs. Where evaluation is unclear a radionuclide thyroid scan may be needed to show homogenous increased uptake in Graves’ disease versus a focal increase in toxic nodules (multi-nodular goiter or adenoma). In thyroiditis and iatrogenic hyperthyroidism (exogenous consumption) the uptake is low or absent [6]. Serum thyroglobulin (Tg) can be used to distinguish thyroiditis (elevated Tg) from iatrogenic hyperthyroidism (normal Tg).

Citation: Huang HL and Aw TC. Thyroid Function Testing – A Review. Annals Thyroid Res. 2014;1(2): 17-22.